Selective androgen receptor degrader (SARD) ligands and methods of use thereof

ABSTRACT

This invention provides novel 3-amino propanamide selective androgen receptor degrader (SARD) compounds, pharmaceutical compositions and uses thereof in treating prostate cancer, advanced prostate cancer, castration resistant prostate cancer, androgenic alopecia or other hyperandrogenic dermal diseases, Kennedy&#39;s disease, amyotrophic lateral sclerosis (ALS), and uterine fibroids, and to methods for reducing the levels of androgen receptor-full length (AR-FL) including pathogenic or resistance mutations, AR-splice variants (AR-SV), and pathogenic polyglutamine (polyQ) polymorphisms of AR in a subject.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation-in-Part application of U.S. patentapplication Ser. No. 15/331,751, filed on Oct. 21, 2016, which is aContinuation-in-Part application of U.S. patent application Ser. No.15/135,151, filed on Apr. 21, 2016, now U.S. Pat. No. 9,815,776, whichclaims the benefit of U.S. Provisional Application Ser. No. 62/220,094,filed on Sep. 17, 2015, and U.S. Provisional Application Ser. No.62/150,768, filed on Apr. 21, 2015, which are incorporated in theirentirety herein by reference.

FIELD OF THE INVENTION

This invention is directed to 3-amino-propanamide selective androgenreceptor degrader (SARD) compounds, pharmaceutical compositions and usesthereof in treating prostate cancer, advanced prostate cancer,castration resistant prostate cancer, androgenic alopecia or otherhyperandrogenic dermal diseases, Kennedy's disease, amyotrophic lateralsclerosis (ALS), and uterine fibroids, and to methods for reducing thelevels of androgen receptor-full length (AR-FL) including pathogenic orresistance mutations, AR-splice variants (AR-SV), and pathogenicpolyglutamine (polyQ) polymorphisms of AR in a subject.

BACKGROUND OF THE INVENTION

Prostate cancer (PCa) is one of the most frequently diagnosednoncutaneous cancers among men in the US and is the second most commoncause of cancer deaths with more than 200,000 new cases and over 30,000deaths each year in the United States. PCa therapeutics market isgrowing at an annual rate of 15-20% globally.

Androgen-deprivation therapy (ADT) is the standard of treatment foradvanced PCa. Patients with advanced prostate cancer undergo ADT, eitherby luteinizing hormone releasing hormone (LHRH) agonists, LHRHantagonists or by bilateral orchiectomy. Despite initial response toADT, disease progression is inevitable and the cancer emerges ascastration-resistant prostate cancer (CRPC). Up to 30% of patients withprostate cancer that undergo primary treatment by radiation or surgerywill develop metastatic disease within 10 years of the primarytreatment. Approximately 50,000 patients a year will develop metastaticdisease, which is termed metastatic CRPC (mCRPC).

Patients with CRPC have a median survival of 12-18 months. Thoughcastration-resistant, CRPC is still dependent on the androgen receptor(AR) signaling axis for continued growth. The primary reason for CRPCre-emergence is re-activation of AR by alternate mechanisms such as 1)intracrine androgen synthesis, 2) AR splice variants (AR-SV) that lackligand binding domain (LBD), 3) AR-LBD mutations with potential toresist AR antagonists (i.e., mutants that are not sensitive toinhibition by AR antagonists, and in some cases AR antagonists act asagonists of the AR bearing these LBD mutations); and 4) amplificationsof the AR gene within the tumor.

A critical barrier to progress in treating CRPC is that AR signalinginhibitors such as enzalutamide, bicalutamide, and abiraterone, actingthrough the LBD, fail to inhibit growth driven by the N-terminal domain(NTD)-dependent constitutively active AR-SV. Recent high-impact clinicaltrials with enzalutamide and abiraterone in CRPC patients demonstratedthat 0% of AR-V7 (the predominant AR-SV) expressing patients respondedto either of the treatments, indicating the requirement for nextgeneration AR antagonists that target AR-SVs. In addition, a significantnumber of CRPC patients are becoming refractory to abiraterone orenzalutamide, emphasizing the need for next generation AR antagonists.

Current evidences demonstrate that CRPC growth is dependent onconstitutively active AR including AR-SV's that lack the LBD such asAR-V7 and therefore cannot be inhibited by conventional antagonists. ARinhibition and degradation through binding to a domain that is distinctfrom the AR LBD provides alternate strategies to manage CRPC.

Molecules that degrade the AR prevent any inadvertent AR activationthrough growth factors or signaling pathways, or promiscuousligand-dependent activation. In addition, molecules that inhibit theconstitutive activation of AR-S Vs are extremely important to provideextended benefit to CRPC patients.

Currently only a few chemotypes are known to degrade AR which includethe SARDs ARN-509, AZD-3514, and ASC-J9. However, these moleculesdegrade AR indirectly at much higher concentrations than their bindingcoefficient and they fail to degrade the AR-S Vs that have become inrecent years the primary reason for resurgence of treatment-resistantCRPC.

This invention describes novel AR antagonists with unique pharmacologythat strongly (high potency and efficacy) and selectively bind AR(better than known antagonists), antagonize AR, and degrade AR fulllength (AR-FL) and AR-SV. Selective androgen receptor degrader (SARD)compounds possess dual degradation and AR-SV inhibitory functions andhence are distinct from any available CRPC therapeutics. These novelselective androgen receptor degrader (SARD) compounds inhibit the growthof PCa cells and tumors that are dependent on AR-FL and AR-SV forproliferation.

SARDs have the potential to evolve as new therapeutics to treat CRPCsthat are untreatable with any other antagonists. This unique property ofdegrading AR-SV has extremely important health consequences for prostatecancer. Till date only one molecule (EPI-001) is reported to bind toAR-NTD and inhibit AR function and PCa cell growth, albeit at loweraffinity and inability to degrade the receptor. The SARDs reportedherein also bind to AR-NTD and inhibit NTD-driven AR activity.

The positive correlation between AR and PCa and the lack of a fail-safeAR antagonist, emphasize the need for molecules that inhibit AR functionthrough novel or alternate mechanisms and/or binding sites, and that canelicit antagonistic activities within an altered cellular environment.

Although traditional antiandrogens such as enzalutamide, bicalutamideand flutamide and androgen deprivation therapies (ADT) were approved foruse in prostate cancer, there is significant evidence that antiandrogenscould also be used in a variety of other hormonal dependent and hormoneindependent cancers. For example, antiandrogens have been tested inbreast cancer (enzalutamide; Breast Cancer Res. (2014) 16(1): R7),non-small cell lung cancer (shRNAi AR) (Mol. Cell Endocrinol. 2010,317(1-2):14-24), renal cell carcinoma (ASC-J9) (Cancer Res. 2014,74(16):4420-30), partial androgen insensitivity syndrome (PAIS)associated malignancies such as gonadal tumors and seminoma, advancedpancreatic cancer (World J. Gastroenterology 20(29):9229), cancer of theovary, fallopian tubes (ClinicalTrials.gov, Identifier: NCT01974765), orperitoneum, cancer of the salivary gland (Head and Neck (2016) 38:724-731; ADT was tested in AR-expressing recurrent/metastatic salivarygland cancers and was confirmed to have benefit on progression freesurvival and overall survival endpoints), esophageal cancer (World J.Gastroenterol, 2015, 21(20):6146-56), bladder cancer (Oncotarget 6 (30):29860-29876; Int J. Endocrinol (2015), Article ID 384860), pancreaticcancer, lymphoma (including mantle cell) (Exp. Hematol. 2017,49:34-38.e2), melanoma (Melanoma Res. 2002, 12(6):529-38), gastriccancer (J. Cancer Res. Clin. Oncol. 2004, 130(5):253-8), colon cancer(Virchows Arch B Cell Pathol. Incl. Mol. Pathol. 1982, 38(3):351-5), andhepatocellular carcinoma (World J. Gastroenterol. 2014, 20(28):9229-36).Use of a more potent antiandrogen such as a SARD in these cancers maytreat the progression of these and other cancers. Many hormonal andnon-hormonal cancers may benefit from SARD treatment such as breastcancer, testicular cancer, cancers associated with partial androgeninsensitivity syndromes (PAIS) such as gonadal tumors and seminoma,uterine cancer, ovarian cancer, cancer of the fallopian tubes orperitoneum, salivary gland cancer, bladder cancer, urogenital cancer,brain cancer, skin cancer, lymphoma, melanoma, mantle cell lymphoma,liver cancer, hepatocellular carcinoma, renal cancer, renal cellcarcinoma, osteosarcoma, pancreatic cancer, esophageal cancer,endometrial cancer, lung cancer, non-small cell lung cancer (NSCLC),gastric cancer, colon cancer, perianal adenoma, or central nervoussystem cancer.

Traditional antiandrogens such as bicalutamide and flutamide wereapproved for use in prostate cancer. Subsequent studies havedemonstrated the utility of antiandrogens (e.g., flutamide,spironolactone, cyproterone acetate, finasteride and chlormadinoneacetate) in androgen-dependent dermatological conditions such asandrogenic alopecia (male pattern baldness), acne vulgaris, andhirsutism. Prepubertal castration prevents sebum production andandrogenic alopecia but this can be reversed by use of testosterone,suggesting its androgen-dependence.

The AR gene has a polymorphism of glutamine repeats (polyQ) within exon1 which when shortened may augment AR transactivation (i.e.,hyperandrogenism). It has been found that shortened polyQ polymorphismsare more common in people with alopecia, hirsutism, and acne. Classicantiandrogens are undesirable for these purposes because they areineffective through dermal dosing and their long-term systemic useraises the risks of untoward sexual effects such as gynecomastia andimpotence. Further, similar to CPRC discussed above, inhibition ofligand-dependent AR activity alone may not be sufficient as AR can beactivated by various cellular factors other than the endogeneousandrogens testosterone (T) and dihydrotestosterone (DHT), such as growthfactors, kinases, co-activator overexpression and/or promiscuousactivation by other hormones (e.g., estrogens or glucocorticoids).Consequently, blocking the binding of T and DHT to AR with a classicalantiandrogen may not be sufficient to have the desired efficacy.

An emerging concept is the topical application of a SARD to destroy theAR locally to the affected areas of the skin or other tissue withoutexerting any systemic antiandrogenism. For this use, a SARD that doesnot penetrate the skin or is rapidly metabolized would be preferable.

Supporting this approach is the observation that cutaneous wound healinghas been demonstrated to be suppressed by androgens. Castration of miceaccelerates cutaneous wound healing while attenuating the inflammationin the wounds. The negative correlation between androgen levels andcutaneous healing and inflammation, in part, explains another mechanismby which high levels of endogenous androgens exacerbate hyperandrogenicdermatological conditions. Further, it provides a rationale for thetreatment of wounds such as diabetic ulcers or even trauma, or skindisorders with an inflammatory component such as acne or psoriasis, witha topical SARD.

Androgenic alopecia occurs in ˜50% of Caucasian males by midlife and upto 90% by 80 years old. Minoxidil (a topical vasodilator) andfinasteride (a systemic 5alpha reductase type II inhibitor) are FDAapproved for alopecia but require 4-12 months of treatment to produce atherapeutic effect and only arrest hair loss in most with mild tomoderate hair regrowth in 30-60%. Since currently available treatmentshave slow and limited efficacy that varies widely between individuals,and produce unwanted sexual side effects, it is important to find anovel approach to treat androgenic alopecia and other hyperandrogenicdermatologic diseases.

Anti-androgens are effective in hyperandrogenic hormonal conditions infemales such as precocious puberty, early puberty, dysmenorrhea,amenorrhea, multilocular uterus syndrome, endometriosis, hysteromyoma,abnormal uterine bleeding, early menarche, fibrocystic breast disease,fibroids of the uterus, ovarian cysts, polycystic ovary syndrome,pre-eclampsia, eclampsia of pregnancy, preterm labor, premenstrualsyndrome, and/or vaginal dryness. These hormonal conditions arehyperandrogenic. For example, hyperandrogenic central precocious puberty(CPP) is discussed in Pediatric Research (1993) 33, S14-S14 or in thePediatric Research supplement (abstract 64) and others are known in theart.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerativedisease. Patients with ALS are characterized by extended ARpolyglutamine repeats. Riluzole is an available drug for ALS treatment,however, only provides short-term effects. There is an urgent need fordrugs that extend the survival of ALS patients. Transgenic animals ofALS were shown to survive longer upon castration and reduction in ARlevels compared to castration+nandrolone (agonist) supplementation.Castration reduces the AR level, which may be the reason for extendedsurvival.

In subjects with amyotrophic lateral sclerosis (ALS), an anti-androgenwould block the toxic effects of nandrolone undecanoate in the castratedmodel, or endogeneous AR agonists in intact ALS subjects, as stimulationwith nandrolone promoted the recruitment of endogenous AR intobiochemical complexes that were insoluble in sodium dodecyl sulfate, afinding consistent with protein aggregation (Neurobiol. Ageing. 201435(8), 1929-1938). The AR degradation activities of the claimed SARDswould lessen the likelihood of forming the pathologic AR aggregates seenin ALS.

Uterine fibroids are also known as leiomyoma. Androgens promote uterineproliferation and the formation of leiomyoma. Leiomyoma has beenassociated with increased mutations in polyQ AR (J. Assist. Reprod.Genet. 2004, 21(12), 453-457; Clin. Chem. Lab. Med. 2008, 46(6),814-823). Degradation of the pathogenic polyQ AR may be preventative ofand therapeutic in leiomyomas. For example, the SWAN study (J. Clin.Endocrinol. Metab. 2016, 101(1), 123-130) established that middle agedwomen with high testosterone had a 33% increased incidence of newuterine fibroids and the risk was further elevated to 52% in those withhigh testosterone and estradiol.

Uterine fibroids are common reproductive-age benign tumors thatcontribute to severe morbidity and infertility. Cumulative incidence is4 times higher in African-Americans compared to Caucasians andconstitutes a major health disparity challenge. Fibroids are the leadingindication for hysterectomy and their management averages $21 billionannually in the US. No long term minimally invasive therapies exist.Thus, promising drug therapies, with novel chemistry and pharmacologicalapproaches are needed to improve clinical efficacy. Androgens promoteuterine proliferation. Higher testosterone levels increase the risk ofuterine fibroids. Treatment of uterine fibroids with SARDs would helpprevent or treat uterine fibroids.

An abdominal aortic aneurysm (AAA) is an enlarged area in the lower partof the aorta, the major blood vessel that supplies blood to the body.The aorta, about the thickness of a garden hose, runs from your heartthrough the center of your chest and abdomen. Because the aorta is thebody's main supplier of blood, a ruptured abdominal aortic aneurysm cancause life-threatening bleeding. Depending on the size and the rate atwhich your abdominal aortic aneurysm is growing, treatment may vary fromwatchful waiting to emergency surgery. Once an abdominal aortic aneurysmis found, doctors will closely monitor it so that surgery can be plannedif it's necessary. Emergency surgery for a ruptured abdominal aorticaneurysm can be risky. AR blockade (pharmacologic or genetic) reducesAAA. Davis et al. (Davis J P, Salmon M, Pope N H, Lu G, Su G, Meher A,Ailawadi G, Upchurch G R Jr. J Vasc Surg (2016) 63(6):1602-1612) showedthat flutamide (50 mg/kg) or ketoconazole (150 mg/kg) attenuated porcinepancreatic elastase (0.35 U/mL) induced AAA by 84.2% and 91.5% comparedto vehicle (121%). Further AR−/− mice showed attenuated AAA growth(64.4%) compared to wildtype (both treated with elastase).Correspondingly, administration of a SARD to a patient suffering from anAAA may help reverse, treat or delay progression of AAA to the pointwhere surgery is needed.

Here we describe 3-amino-propanamide SARDs that bind to LBD and analternate binding and degradation domain (BDD; located in the NTD),antagonize AR, and degrade AR thereby blocking ligand-dependent andligand-independent AR activities. This novel mechanism produces improvedefficacy when dosed systemically (e.g., for prostate cancer) ortopically (e.g., dermatological diseases). X-linked spinal-bulbarmuscular atrophy (SBMA—also known as Kennedy's disease) is a muscularatrophy that arises from a defect in the androgen receptor gene on the Xchromosome. Proximal limb and bulbar muscle weakness results in physicallimitations including dependence on a wheelchair in some cases. Themutation results in a protracted polyglutamine tract added to theN-terminal domain of the androgen receptor (polyQ AR). Binding andactivation of this lengthened polyQ AR by endogeneous androgens(testosterone and DHT) results in unfolding and nuclear translocation ofthe mutant androgen receptor. These steps are required for pathogenesisand result in partial loss of transactivation function (i.e., anandrogen insensitivity) and a poorly understood neuromusculardegeneration.

Currently there are no disease-modifying treatments, but rather onlysymptom directed treatments. Efforts to target the polyQ AR of Kennedy'sdisease as the proximal mediator of toxicity by harnessing cellularmachinery to promote its degradation, i.e., through the use of a SARD,hold promise for therapeutic intervention. Selective androgen receptordegraders such as those reported herein bind to and degrade a variety ofandrogen receptors (full length, splice variant, antiandrogen resistancemutants, and are likely to degrade polyQ AR polymorphism as well),indicating that they are promising leads for treatment of SBMA. SARDsthat degrade the pathogenic polyQ AR likely provide advantages overnon-SARD anti-androgens such as flutamide.

SUMMARY OF THE INVENTION

In one aspect, the invention provides a method of treating, suppressing,reducing the incidence, reducing the severity, or inhibiting theprogression of AR-expressing cancer in a subject, comprisingadministering to said subject a therapeutically effective amount ofcompound 17

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In one embodiment, AR-expressing cancer is a cancer associated withpartial androgen insensitivity syndromes (PAIS), cancer of the fallopiantubes or peritoneum, salivary gland cancer, esophageal cancer, bladdercancer, melanoma, mantle cell lymphoma, hepatocellular carcinoma, renalcell carcinoma, non-small cell lung cancer (NSCLC), gastric cancer, orcolon cancer. In one embodiment, the cancer associated with partialandrogen insensitivity syndromes (PAIS) is gonadal tumors and/orseminoma.

In one aspect, the invention provides a method of treating, suppressing,reducing the incidence, reducing the severity, or inhibiting theprogression of Kennedy's disease in a subject, comprising administeringto said subject a therapeutically effective amount of compound 17

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In another aspect, the invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of amyotrophic lateral sclerosis (ALS) in asubject, comprising administering to said subject a therapeuticallyeffective amount of compound

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In another aspect, the invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of AR-positive cancer that is resistant totreatment with an androgen receptor antagonist and/or a lyase inhibitor,comprising administering to said subject a therapeutically effectiveamount of compound 17

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In another aspect, the invention provides a method of treating abdominalaortic aneurysm (AAA) in a subject, comprising administering to saidsubject a therapeutically effective amount of compound 17

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In another aspect, the invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of a hyperandrogenic hormonal condition in afemale, comprising administering to said subject a therapeuticallyeffective amount of compound 17

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In one embodiment, the hyperandrogenic hormonal condition in a female isprecocious puberty, early puberty, dysmenorrhea, amenorrhea,multilocular uterus syndrome, endometriosis, hysteromyoma, abnormaluterine bleeding, early menarche, fibrocystic breast disease, fibroidsof the uterus, ovarian cysts, polycystic ovary syndrome, pre-eclampsia,eclampsia of pregnancy, preterm labor, premenstrual syndrome, and/orvaginal dryness.

In another aspect, the invention provides a topical pharmaceuticalcomposition comprising compound 17

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof, and a pharmaceuticallyacceptable carrier.

In one embodiment, the topical pharmaceutical composition is in the formof a solution, lotion, salve, cream, ointment, liposome, spray, gel,foam, roller stick, cleansing soap or bar, emulsion, mousse, aerosol,shampoo, or any combination thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

The subject matter regarded as the invention is particularly pointed outand distinctly claimed in the concluding portion of the specification.The invention, however, both as to organization and method of operation,together with objects, features, and advantages thereof, may best beunderstood by reference to the following detailed description when readwith the accompanying drawings in which:

FIG. 1 depicts the effect of novel AR antagonists on AR protein levels(i.e. the SARD effect). (A) Serum-starved LNCaP cells treated with R1881and SARD compound (17). (B) Dose response of 17 in the presence of 0.1nM R1881 in LNCaP cells. (C) LNCaP cells were plated in full serum andtreated with compound 17 (dose response). Cells were harvested, proteinextracted, and Western blotted for AR and actin. (D) Effect of 17 onwild-type AR transfected into HeLa cells. (E) Effect of 14 on ARexpression in VCaP. (F) Time-course response of AR to SARD (14) in LNCaPcells. 17-AAG-17-allylamino-17-demethoxygeldanamycin, a Hsp90 inhibitor.MDV-3100, an AR antagonist (antiandrogen) also known as enzalutamide.AR—androgen receptor; R1881—an AR agonist.

FIG. 2A and FIG. 2B depict the AR degradation by SARD compound 17 inLNCaP cells. (A) LNCaP cells were plated in serum free medium andtreated with the indicated concentrations of compound 17 and ARN-509 inthe presence or absence of R1881. Cells were harvested, proteinextracted and Western blotted for AR and actin. (B) LNCaP cells wereplated in 96 well plates at 10,000 cells/well in RPMI+1% csFBS withoutphenol red. Cells were treated as indicated above in combination with0.1 nM R1881 for 6 days with medium change on day 3. At the end of 6days, the cells were fixed and stained with sulphorhodamine blue stainto measure cell growth. Enzalutamide and ARN-509 are other ARantagonists reported to degrade AR.

FIG. 3 depicts the effect of SARDs on AR-FL and AR-SV protein levels.(A) and (B) SARD 17 degrades AR full length and splice variant in 22RV-1cells. 22RV-1 cells were plated in serum free medium and treated withthe indicated concentrations of compound 17, ARN-509 or ASC-J9 in thepresence or absence of R1881. Cells were harvested, protein extractedand Western blotted for AR and actin. Blots were quantified usingImage-J (panel B). (C) Same experiment repeated with compound 14.AR-FL—androgen receptor-full length; AR-V7—androgen receptor splicevariant 7 (lacks ligand binding domain); ARN-509 and ASC-J9 are other ARantagonists reported to degrade AR.

FIG. 4 depicts degradation of AR by SARDs under varying conditions(A-D), without degradation of other receptors (E-F). (A) and (B) LNCaPcells were serum starved and treated with compound 17 (10 uM in panel Aand a dose response in panel B) in the presence or absence of R1881.Bicalutamide was used as a negative control. Cells were harvested,protein extracted, and Western blotted for AR and actin. (C) LNCaP cellswere plated in full serum and treated with compound 17 (dose response).Cells were harvested, protein extracted, and Western blotted for AR andactin. (D) HeLa cells were infected with adenovirus containing AR andwere treated with compound 17 in the presence or absence of R1881. Cellswere harvested, protein extracted, and Western blotted for AR and actin.(E) and (F) SARDs do not degrade other nuclear receptors. T47D (leftpanel) and MCF-7 (right panel) cells were plated in full serum andtreated with compound 17 (dose response). Cells were harvested, proteinextracted, and Western blotted for PR (progesterone receptor) or ER-α(estrogen receptor-alpha) and actin.

FIG. 5 depicts the effect of SARDs 17 and 14 on AR-target tissues (SV orS.V.—seminal vesicles and prostate) in the Hershberger assay. Thenumbers at the bottom of the graphs are the area under the curve (AUC)for drug concentration.

FIG. 6 depicts that SARDs do not inhibit transactivation of otherreceptors until 10 uM. HEK-293 cells were transfected with the indicatedreceptors and GRE-LUC and CMV-renilla luc. Cells were treated with 17for 24 hrs after transfection and luciferase assay performed 48 hrsafter transfection. GR—glucocorticoid receptor; Dex—dexamethasone;MR—mineralocorticoid receptor; Ald—aldosterone; PR—progesteronereceptor; and Prog—progesterone.

FIG. 7 depicts that SARD treatment inhibited AR recruitment to thepromoter of androgen responsive genes (PSA, FKBP, & TMPRSS2) and loweredAR levels in the nucleus in R1881 treated animals. (A) LNCaP cells wereserum starved for 3 days and treated as indicated above with SARD (17)or bicalutamide at 10 uM in the presence or absence of 0.1 nM R1881.Proteins were cross-linked to DNA and chromatin immunoprecipitationstudies were conducted with AR and RNA-Pol II antibodies. (B) SARDsdegrade AR. LNCaP cells were serum starved for 3 days and treated asindicated above with SARD (17) at 10 uM in the presence or absence of0.1 nM R1881. Cells were fixed and immunofluorescence for AR performed.Nucleus was stained with DAPI.

FIG. 8 depicts that SARDs inhibit LNCaP cell growth by non-competitivebinding of AR. LNCaP cells were plated in serum free medium and weretreated with increasing concentrations of enzalutamide or compound 17 inthe presence of a dose range of R1881. Seven days after treatment, cellswere fixed and growth measured by WST-1 assay.

FIG. 9 depicts that 49 in the presence of R1881 degrades AR in LNCaPcells. LNCaP cells were plated in 6 well plates at 1 million cells/well.The cells were maintained in serum free conditions for 3 days. The cellswere treated as indicated in the figure, harvested, protein extracted,and Western blotted for AR. 49 (and other SARDs disclosed herein)demonstrated selective degradation of AR (i.e., SARD activity) in the nMrange, i.e., at concentrations comparable to their antagonist IC₅₀values. LNCaP cells are known to express the AR mutant T877A,demonstrating the ability of SARDs of this invention to degradeantiandrogen resistance conferring mutant androgen receptors.

FIG. 10 depicts that 49 degrades AR in RV22-1 cells. 22RV-1 cells wereplated in a 6 well plate at 1-1.5 million cells/well in growth medium(RPMI+10% FBS). Next day, medium was changed and treated with vehicle ora dose response of 49. After overnight treatment (12-16 hrs), cells werewashed in ice cold PBS and harvested by scrapping in 1 mL PBS. Cellswere pelleted, protein extracted, quantified using BCA assay, and equalquantity of protein was fractionated on a SDS-PAGE. The proteins weretransferred to nylon membrane and Western blotted with AR antibody (N20from SCBT) and actin antibody. 49 (and other SARDs disclosed herein) wascapable of degrading full-length androgen receptor (AR-FL) and truncatedAR (AR-SV) in 22RV-1 cells, suggesting that SARDs of this invention maybe able to overcome AR-V7 dependent prostate cancers.

FIGS. 11A-11B depict that SARDs bind to the N-terminal activationfunction 1 of AR (AR-AF1) in addition to the C-terminal ligand bindingdomain (LBD) which contains the AR-AF2. FIG. 11A: There are twotryptophan residues and up to 12 tyrosine residues. This has allowed usto study the folding properties of this domain using intrinsic steadystate fluorescence emission spectra. Excitation at 287 nm excites bothtyrosine and tryptophan residues. The emission maximum (κ_(max)) for thetryptophan is sensitive to the exposure to solvent. In the presence ofthe natural osmolyte TMAO (AF1+TMAO) there is a characteristic ‘blueshift’ consistent with the tryptophan residues being less solventexposed and a loss of the shoulder (˜307 nm; see solid black trace ascompared to AF1 (alone) which is the 2^(nd) to top trace at 300 nm inthe left panel and top trace at 300 nm in the right panel) for tyrosineas there is increased energy transfer to tryptophan as the polypeptidefolds. In contrast in the presence of urea (causes unfolding) there is a‘red shift’ as the tryptophan residues become more solvent exposed and adefined peak for tyrosine emission appears. To test if the compounds(enobosarm (E) and 17) interact with AF-1 and/or alter the folding ofthis domain we measured the steady state fluorescence for each compoundwith AR-AF1 alone or the presence of TMAO (3 M) or urea (4 or 6 M).Enobosarm was used as a negative control (should not interact) whileTMAO serves as a positive control (should promote folding). We used 1 μMof AR-AF1 and 5 μM of the individual compounds and preincubated for atleast 30 minutes prior to measuring the emission spectra. The emissionspectra were all corrected for buffer alone or buffer withTMAO/urea/compounds as necessary. There was no dramatic effect ofenobosarm (left panel) on the λ_(max) for tryptophan, while 17 (rightpanel) reduces the wavelength (i.e., a ‘blue shift’), indicating that 17binds to the AF-1 and enobosarm does not bind to AF-1. Also, theshoulder is missing on the AF1+TMAO+17 trace. FIG. 11B: Left Panel: Adose-dependent shift in the fluorescence intensity (i.e., quenching) by17 was observed when incubated with AR AF-1. The fluorescence shoulderobserved at 307 nm, which corresponds to tyrosine residues in the AF-1,is shifted by 17. The overall fluorescence is also markedly altered by17. This indicates that 17 interacts with the AR AF-1 (in addition tothe LBD binding demonstrated in other experiments). Right Panel. Datashown in the left panel was plotted as a difference in fluorescence plotbetween control and 17 treated samples (fluorescence in the absence ofcompound—fluorescence in the presence of compound), a dose dependentincrease was observed in the presence of 17, again supporting that 17interacts with the AR AF-1. AF1—activation function-1 which is a domainin the NTD of AR; TMAO—trimethylamine-N-oxide; E—enobosarm which is aselective androgen receptor modulator which does not bind NTD; 17—aselective androgen receptor degrader (SARD) of this invention.

FIG. 12 depicts biolayer—interferometry (BLI) raw data measurements ofAF1 binding to compound 17 at the concentration of 50 nM. The first 60seconds are baseline (does not start at 0), followed by 300 seconds ofan association and dissociation phase (˜1650-1950 on y-axis). AF1 loadedbiosensors are the top two traces. Addition of 17 to AF-1 loaded sheetscauses a stronger shift as compared to controls loaded with ERD14 andbiocytin (bottom two traces) as reference sensors suggesting that 17 hasa direct interaction with AF-1 at concentrations as low as 50 nM.

FIGS. 13A-13C depict inhibitory AR function of 17. 17 potently inhibitedAR transactivation. AR transactivation was performed by transfectinghuman AR cDNA, GRE-LUC, and CMV-renilla LUC into HEK-293 cells. Cellswere treated 24 hrs after transfection with a dose response of 17 and0.1 nM R1881 and luciferase assay was performed 48 hrs aftertransfection. Values provided are IC₅₀. (FIG. 13A). 17 comparablyinhibited transactivation of wildtype and LBD-mutant AR. Transactivationassay with 17 was performed with wildtype AR or AR carrying commonlyknown LBD mutants. (FIG. 13B). 17 does not cross-react withmineralocorticoid receptor (MR) or glucocorticoid receptor (GR).Transactivation was performed by transfecting human AR, GR, or MR cDNA,GRE-LUC, and CMV-renilla LUC into HEK-293 cells. Cells were treated 24hrs after transfection with indicated doses of 17 in combination with0.1 nM R1881 (AR), dexamethasone (GR) and aldosterone (MR) andluciferase assay was performed 48 hrs after transfection. (FIG. 13C). 17potently inhibited the expression of AR-target genes in LNCaP cells.LNCaP cells were maintained in charcoal stripped serum containing mediumfor two days and treated with vehicle or indicated compounds (17 orenzalutamide with concentration range between 1 and 10,000 nM) in thepresence of 0.1 nM R1881. RNA was isolated and expression of PSA (notshown) or FKBP5 was quantified and normalized to GAPDH by realtime PCR(FIG. 13D).

FIGS. 14A-14B depict degradation of AR using 17 under multipleconditions. LNCaP cells were maintained in charcoal stripped serumcontaining medium for 2 days and treated as indicated in the figure for24 hrs. Western blot for the AR with N20 antibody and actin wasperformed (FIG. 14A). LNCaP cells were maintained in charcoal strippedserum containing medium for 2 days and treated with vehicle or 17 in thepresence of 0.1 nM R1881. Western blot for the AR with AR C19 antibodyand actin was performed (FIG. 14B).

FIG. 15 shows that 17 does not inhibit AR mRNA. LNCaP cells weremaintained in charcoal stripped serum containing medium for two days andtreated for 24 hours with vehicle or 17 (0.001-10,000 nM) in thepresence of 0.1 nM R1881. RNA was isolated and expression of AR or FKBP5was quantified and normalized to GAPDH by realtime PCR.

FIGS. 16A-16B depict inhibition of DNA binding of the AR and RNA Pol IIusing 17. LNCaP cells were serum starved for 2 days and were treatedwith 0.1 nM R1881 in the presence or absence of 10 μM 17 or bicalutamide(Bical) for 2 hrs. DNA-protein complex was cross-linked and AR (FIG.16A) and RNA Pol II (FIG. 16B) were immunoprecipitated and theirrecruitment to PSA regulatory regions was measured by realtime PCR. N=3.Values are expressed as average±S.E.

It will be appreciated that for simplicity and clarity of illustration,elements shown in the figures have not necessarily been drawn to scale.For example, the dimensions of some of the elements may be exaggeratedrelative to other elements for clarity. Further, where consideredappropriate, reference numerals may be repeated among the figures toindicate corresponding or analogous elements.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

In the following detailed description, numerous specific details are setforth in order to provide a thorough understanding of the invention.However, it will be understood by those skilled in the art that thepresent invention may be practiced without these specific details. Inother instances, well-known methods, procedures, and components have notbeen described in detail so as not to obscure the present invention.

Androgens act in cells by binding to the AR, a member of the steroidreceptor superfamily of transcription factors. As the growth andmaintenance of prostate cancer (PCa) is largely controlled bycirculating androgens, treatment of PCa heavily relies on therapies thattarget AR. Treatment with AR antagonists such as enzalutamide,bicalutamide or hydroxyflutamide to disrupt receptor activation has beensuccessfully used in the past to reduce PCa growth. All currentlyavailable AR antagonists competitively bind AR and recruit corepressorssuch as NCoR and SMRT to repress transcription of target genes. However,altered intracellular signaling, AR mutations, and increased expressionof coactivators lead to functional impairment of antagonists or eventransformation of antagonists into agonists. Studies have demonstratedthat mutation of W741 and T877 within AR converts bicalutamide andhydroxyflutamide, respectively, to agonists. Similarly, increasedintracellular cytokines recruit coactivators instead of corepressors toAR-responsive promoters subsequently converting bicalutamide to anagonist.

Despite initial response to androgen deprivation therapy (ADT), PCadisease progression is inevitable and the cancer emerges ascastration-resistant prostate cancer (CRPC). The primary reason forcastration resistant prostate cancer (CRPC) re-emergence isre-activation of androgen receptor (AR) by alternate mechanisms such as:

-   -   (a) intracrine androgen synthesis;    -   (b) expression of AR splice variants (AR-SV) that lack ligand        binding domain (LBD);    -   (c) AR-LBD mutations with potential to resist antagonists;    -   (d) hyper-sensitization of AR to low androgen levels, e.g., due        to AR gene amplification or AR mutation;    -   (e) amplification of the AR gene within the tumor; and    -   (f) over expression of coactivators.

In one embodiment, this invention is directed to novel selectiveandrogen receptor degrader (SARD) compounds, which inhibit the growth ofprostate cancer (PCa) cells and tumors that are dependent on AR fulllength (AR-FL) including pathogenic and resistance mutations andwildtype, and AR splice variants (AR-SV) for proliferation.

According to this invention, a “selective androgen receptor degrader”(SARD) compound is an androgen receptor antagonist that is capable ofinhibiting the growth of PCa cells and tumors that are dependent onAR-full length (AR-FL) and/or AR splice variants (AR-SV) forproliferation. In another embodiment, the SARD compound does not bind toligand binding domain (LBD). In another embodiment, the SARD compoundbinds to the N-terminal domain (NTD) of the AR. In another embodiment,the SARD compound binds to an alternate binding and degradation domain(BDD) of the AR. In another embodiment, the SARD compound binds both tothe AR ligand binding domain (LBD) and to an alternate binding anddegradation domain (BDD). In another embodiment, the SARD compound bindsboth to the N-terminal domain (NTD) and to the ligand binding domain(LBD) of the AR. In another embodiment, the SARD compound is capable ofinhibiting growth driven by the N-terminal domain (NTD)-dependentconstitutively active AR-SV. In another embodiment, the SARD compoundinhibits the AR through binding to a domain that is distinct from the ARLBD. In another embodiment, the SARD compound is a strong (i.e., highlypotent and highly efficacious) selective androgen receptor antagonist,which antagonizes the AR stronger than other known AR antagonists (e.g.,enzalutamide, bicalutamide and abiraterone). In another embodiment, theSARD compound is a selective androgen receptor antagonist, which targetsAR-SVs, which cannot be inhibited by conventional antagonists. Inanother embodiment, the SARD compound exhibits AR-splice variant (AR-SV)degradation activity. In another embodiment, the SARD compound furtherexhibits AR-full length (AR-FL) degradation activity. In anotherembodiment, the SARD compound exhibits AR-splice variant (AR-SV)inhibitory activity (i.e., is an AR-SV antagonist). In anotherembodiment, the SARD compound further exhibits AR-full length (AR-FL)inhibitory activity (i.e., is an AR-FL antagonist). In anotherembodiment, the SARD compound possesses dual AR-SV degradation and AR-SVinhibitory functions. In another embodiment, the SARD compound furtherpossesses dual AR-FL degradation and AR-FL inhibitory functions. Inanother embodiment, the SARD compound is a selective androgen receptorantagonist, which targets AR-SVs. In another embodiment, the SARDcompound further targets AR-FLs. In another embodiment, the SARDcompound inhibits the constitutive activation of AR-SVs. In anotherembodiment, the SARD compound further inhibits the constitutiveactivation of AR-FLs. In another embodiment, the SARD compound is aselective androgen receptor antagonist, which degrades AR-full length(AR-FL) and AR splice variants (AR-SV). In another embodiment, the SARDcompound degrades the AR through binding to a domain that is distinctfrom the AR LBD. In another embodiment, the SARD compound possesses dualdegradation and AR-SV inhibitory functions that are distinct from anyavailable CRPC therapeutics. In another embodiment, the SARD compoundinhibits the re-activation of the AR by alternate mechanisms such as:intracrine androgen synthesis, expression of AR splice variants (AR-SV)that lack ligand binding domain (LBD) and AR-LBD mutations withpotential to resist antagonists. In another embodiment, the SARDcompound inhibits re-activated androgen receptors presence in pathogenicaltered cellular environments.

Nonlimiting examples of AR-splice variants (AR-SVs) are: AR-V7 andARv567es (a.k.a. AR-V12). Nonlimiting examples of AR mutationsconferring antiandrogen resistance are: W741L mutation and T877Amutation. AR-V7 is a splice variant of AR that lacks the LBD. It isconstitutively active and has been demonstrated to be responsible foraggressive PCa and resistance to endocrine therapy.

In one embodiment, this invention is directed to novel selectiveandrogen receptor degrader (SARD) compounds, which bind to the ARthrough an alternate binding and degradation domain (BDD). In anotherembodiment, the SARDs further binds the AR ligand binding domain (LBD).

In one embodiment, this invention is directed to novel selectiveandrogen receptor degrader (SARD) compounds, which exhibit AR-splicevariant (AR-SV) inhibitory activity (i.e., is an AR-SV antagonist). Inanother embodiment, the novel selective androgen receptor degrader(SARD) compounds, further exhibit AR-full length (AR-FL) inhibitoryactivity (i.e., is an AR-FL antagonist).

In one embodiment, this invention is directed to novel selectiveandrogen receptor degrader (SARD) compounds, which exhibit AR-splicevariant (AR-SV) degradation activity. In another embodiment, the novelselective androgen receptor degrader (SARD) compounds, further exhibitAR-full length (AR-FL) degradation activity.

In one embodiment, this invention is directed to novel selectiveandrogen receptor degrader (SARD) compounds, which possess dual AR-SVdegradation and AR-SV inhibitory functions. In another embodiment, theSARDs further possess dual AR-FL degradation and AR-FL inhibitoryfunctions. In another embodiment, this invention is directed to novelselective androgen receptor degrader (SARD) compounds, which possessdual AR-SV and AR-FL degradation, and AR-SV and AR-FL inhibitoryfunctions.

In one embodiment, this invention is directed to novel selectiveandrogen receptor degrader (SARD) compounds, for use in treating CRPCthat cannot be treated with any other antagonist.

In one embodiment, this invention is directed to selective androgenreceptor degrader (SARD) compounds, for use in treating CRPC, bydegrading AR-SVs.

In one embodiment, the novel SARD compounds according to this inventionmaintain their antagonistic activity in AR mutants that normally convertAR antagonists to agonists. In another embodiment, the SARD compoundsmaintain their antagonistic activity to AR mutants W741 and T877. Inanother embodiment, the SARD compounds elicit antagonistic activitywithin an altered cellular environment in which LBD-targeted agents arenot effective. In another embodiment, the SARD compounds elicitantagonistic activity within an altered cellular environment in whichNTD-dependent AR activity is constitutively active.

Selective Androgen Receptor Degrader (SARD) Compounds

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula I:

wherein

-   -   T is OH, OR, —NHCOCH₃, or NHCOR;    -   Z is NO₂, CN, COOH, COR, NHCOR or CONHR;    -   Y is CF₃, F, I, Br, Cl, CN, C(R)₃ or Sn(R)₃;    -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,        CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;    -   R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;    -   R2 is hydrogen, C₁-C₁₂-alkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl,        arylalkyl, benzyl, aryl, or C₃-C₇-cycloalkyl;    -   Q₁, Q₂, Q₃, Q₄, and Q₅ are each independently selected from        hydrogen, substituted or unsubstituted linear or branched alkyl,        substituted or unsubstituted aryl, substituted or unsubstituted        phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted arylalkyl, C(R)₃, N(R)₂, NHCOCH₃,        NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,        NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R, SO₂R,        SR, NCS, SCN, NCO, or OCN; or its isomer, pharmaceutically        acceptable salt, pharmaceutical product, polymorph, hydrate or        any combination thereof;    -   wherein at least two of Q₁, Q₂, Q₃, Q₄, and Q₅ are not        hydrogens; or    -   Q₁ and Q₂ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring, and Q₃,        Q₄, and Q₅ are as defined above; or    -   Q₂ and Q₃ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring, and Q₁,        Q₄, and Q₅ are as defined above; and    -   wherein said formed carbocyclic or heterocyclic ring is not        dihydropyridin-2(1H)-one, pyridin-2(1H)-one or 1H-pyrrole.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula IA:

wherein

-   -   T is OH, OR, —NHCOCH₃, or NHCOR;    -   Z is NO₂, CN, COOH, COR, NHCOR or CONHR;    -   Y is CF₃, F, I, Br, Cl, CN, C(R)₃ or Sn(R)₃;    -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,        CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;    -   R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;    -   R₂ is hydrogen, C₁-C₁₂-alkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl,        arylalkyl, benzyl, aryl, or C₃-C₇-cycloalkyl;    -   Q₁, Q₂, Q₃, Q₄, and Q₅ are each independently selected from        hydrogen, substituted or unsubstituted linear or branched alkyl,        substituted or unsubstituted aryl, substituted or unsubstituted        phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted arylalkyl, C(R)₃, N(R)₂, NHCOCH₃,        NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,        NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R, SO₂R,        SR, NCS, SCN, NCO, or OCN; or its isomer, pharmaceutically        acceptable salt, pharmaceutical product, polymorph, hydrate or        any combination thereof;    -   wherein at least two of Q₁, Q₂, Q₃, Q₄, and Q₅ are not        hydrogens; or    -   Q₁ and Q₂ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring, and Q₃,        Q₄, and Q₅ are as defined above; or    -   Q₂ and Q₃ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring, and Q₁,        Q₄, and Q₅ are as defined above; and    -   wherein said formed carbocyclic or heterocyclic ring is not        dihydropyridin-2(1H)-one, pyridin-2(1H)-one or 1H-pyrrole.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula IB:

wherein

-   -   T is OH, OR, —NHCOCH₃, or NHCOR;    -   Z is NO₂, CN, COOH, COR, NHCOR or CONHR;    -   Y is CF₃, F, I, Br, Cl, CN, C(R)₃ or Sn(R)₃;    -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,        CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;    -   R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;    -   R₂ is hydrogen, C₁-C₁₂-alkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl,        arylalkyl, benzyl, aryl, or C₃-C₇-cycloalkyl;    -   Q₁, Q₂, Q₃, Q₄, and Q₅ are each independently selected from        hydrogen, substituted or unsubstituted linear or branched alkyl,        substituted or unsubstituted aryl, substituted or unsubstituted        phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted arylalkyl, C(R)₃, N(R)₂, NHCOCH₃,        NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,        NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R, SO₂R,        SR, NCS, SCN, NCO, or OCN;    -   or its isomer, pharmaceutically acceptable salt, pharmaceutical        product, polymorph, hydrate or any combination thereof;    -   wherein at least two of Q₁, Q₂, Q₃, Q₄, and Q₅ are not        hydrogens; or    -   Q₁ and Q₂ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring, and Q₃,        Q₄, and Q₅ are as defined above; or    -   Q₂ and Q₃ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring, and Q₁,        Q₄, and Q₅ are as defined above; and    -   wherein said formed carbocyclic or heterocyclic ring is not        dihydropyridin-2(1H)-one, pyridin-2(1H)-one or 1H-pyrrole.

In one embodiment, this invention provides a selective androgen receptordegrader (SARD) compound represented by the structure of formula II:

wherein

-   -   T is OH, OR, —NHCOCH₃, or NHCOR;    -   Z is NO₂, CN, COOH, COR, NHCOR or CONHR;    -   Y is CF₃, F, I, Br, Cl, CN, C(R)₃ or Sn(R)₃;    -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,        CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH; R₁ is        CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;    -   R₂ is hydrogen, C₁-C₁₂-alkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl,        arylalkyl, substituted or unsubstituted benzyl, substituted or        unsubstituted aryl, or C₃-C₇-cycloalkyl;    -   Q₁, Q₂, Q₃, Q₄, and Q₅ are each independently selected from        hydrogen, substituted or unsubstituted linear or branched alkyl,        substituted or unsubstituted aryl, substituted or unsubstituted        phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted arylalkyl, C(R)₃, N(R)₂, NHCOCH₃,        NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,        NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R, SO₂R,        SR, NCS, SCN, NCO, or OCN;    -   or its isomer, pharmaceutically acceptable salt, pharmaceutical        product, polymorph, hydrate or any combination thereof;    -   wherein at least two of Q₁, Q₂, Q₃, Q₄, and Q₅ are not        hydrogens; or    -   Q₁ and Q₂ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring, and Q₃,        Q₄, and Q₅ are as defined above; or    -   Q₂ and Q₃ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring, and Q₁,        Q₄, and Q₅ are as defined above; and wherein said formed        carbocyclic or heterocyclic ring is not        dihydropyridin-2(1H)-one, pyridin-2(1H)-one or 1H-pyrrole.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula IIA:

wherein

-   -   T is OH, OR, —NHCOCH₃, or NHCOR;    -   Z is NO₂, CN, COOH, COR, NHCOR or CONHR;    -   Y is CF₃, F, I, Br, Cl, CN, C(R)₃ or Sn(R)₃;    -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,        CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;    -   R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;    -   R₂ is hydrogen, C₁-C₁₂-alkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl,        arylalkyl, benzyl, aryl, or C₃-C₇-cycloalkyl;    -   Q₁ is hydrogen, substituted or unsubstituted linear or branched        alkyl, substituted or unsubstituted aryl, substituted or        unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R)₃,        N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R, SR, NCS, SCN, NCO, or OCN;    -   Q₂ is hydrogen, substituted or unsubstituted linear or branched        alkyl, substituted or unsubstituted aryl, substituted or        unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R)₃,        N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R, SR, NCS, SCN, NCO, or OCN;    -   Q₃ is hydrogen, substituted or unsubstituted linear or branched        alkyl, substituted or unsubstituted aryl, substituted or        unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R)₃,        N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R, SR, NCS, SCN, NCO, or OCN; or its isomer, pharmaceutically        acceptable salt, pharmaceutical product, polymorph, hydrate or        any combination thereof;    -   wherein at least two of Q₁, Q₂ and Q₃ are not hydrogens; or    -   Q₁ and Q₂ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring and Q₃ is        as defined above; or    -   Q₂ and Q₃ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring and Q₁ is        as defined above; and    -   wherein said formed carbocyclic or heterocyclic ring is not        dihydropyridin-2(1H)-one, pyridin-2(1H)-one or 1H-pyrrole.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula IIA:

wherein

-   -   T is OH, OR, —NHCOCH₃, or NHCOR;    -   Z is NO₂, CN, COOH, COR, NHCOR or CONHR;    -   Y is CF₃, F, I, Br, Cl, CN, C(R)₃ or Sn(R)₃;    -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,        CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;    -   R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;    -   R₂ is hydrogen, C₁-C₁₂-alkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl,        arylalkyl, benzyl, aryl, or C₃-C₇-cycloalkyl;    -   Q₁ is hydrogen, substituted or unsubstituted linear or branched        alkyl, substituted or unsubstituted aryl, substituted or        unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R)₃,        N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R, SR, NCS, SCN, NCO, or OCN;    -   Q₂ is hydrogen, substituted or unsubstituted linear or branched        alkyl, substituted or unsubstituted aryl, substituted or        unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R)₃,        N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R, SR, NCS, SCN, NCO, or OCN;    -   Q₃ is hydrogen, substituted or unsubstituted linear or branched        alkyl, substituted or unsubstituted aryl, substituted or        unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R)₃,        N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R, SR, NCS, SCN, NCO, or OCN; or its isomer, pharmaceutically        acceptable salt, pharmaceutical product, polymorph, hydrate or        any combination thereof;    -   wherein at least two of Q₁, Q₂ and Q₃ are not hydrogens; or    -   Q₁ and Q₂ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring and Q₃ is        as defined above; or    -   Q₂ and Q₃ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring and Q₁ is        as defined above; and    -   wherein said formed carbocyclic or heterocyclic ring is not        dihydropyridin-2(1H)-one, pyridin-2(1H)-one or 1H-pyrrole.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula IIB:

wherein

-   -   T is OH, OR, —NHCOCH₃, or NHCOR;    -   Z is NO₂, CN, COOH, COR, NHCOR or CONHR;    -   Y is CF₃, F, I, Br, Cl, CN, C(R)₃ or Sn(R)₃;    -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,        CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;    -   R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;    -   R₂ is hydrogen, C₁-C₁₂-alkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl,        arylalkyl, benzyl, aryl, or C₃-C₇-cycloalkyl;    -   Q₁ is hydrogen, substituted or unsubstituted linear or branched        alkyl, substituted or unsubstituted aryl, substituted or        unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R)₃,        N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R, SR, NCS, SCN, NCO, or OCN;    -   Q₂ is hydrogen, substituted or unsubstituted linear or branched        alkyl, substituted or unsubstituted aryl, substituted or        unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R)₃,        N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R, SR, NCS, SCN, NCO, or OCN;    -   Q₃ is hydrogen, substituted or unsubstituted linear or branched        alkyl, substituted or unsubstituted aryl, substituted or        unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R)₃,        N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R, SR, NCS, SCN, NCO, or OCN; or its isomer, pharmaceutically        acceptable salt, pharmaceutical product, polymorph, hydrate or        any combination thereof;    -   wherein at least two of Q₁, Q₂ and Q₃ are not hydrogens; or    -   Q₁ and Q₂ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring and Q₃ is        as defined above; or    -   Q₂ and Q₃ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring and Q₁ is        as defined above; and    -   wherein said formed carbocyclic or heterocyclic ring is not        dihydropyridin-2(1H)-one, pyridin-2(1H)-one or 1H-pyrrole.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula IIB:

wherein

-   -   T is OH, OR, —NHCOCH₃, or NHCOR;    -   Z is NO₂, CN, COOH, COR, NHCOR or CONHR;    -   Y is CF₃, F, I, Br, Cl, CN, C(R)₃ or Sn(R)₃;    -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,        CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;    -   R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;    -   R₂ is hydrogen, C₁-C₁₂-alkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl,        arylalkyl, benzyl, aryl, or C₃-C₇-cycloalkyl;    -   Q₁ is hydrogen, substituted or unsubstituted linear or branched        alkyl, substituted or unsubstituted aryl, substituted or        unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R)₃,        N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R, SR, NCS, SCN, NCO, or OCN;    -   Q₂ is hydrogen, substituted or unsubstituted linear or branched        alkyl, substituted or unsubstituted aryl, substituted or        unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R)₃,        N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R, SR, NCS, SCN, NCO, or OCN;    -   Q₃ is hydrogen, substituted or unsubstituted linear or branched        alkyl, substituted or unsubstituted aryl, substituted or        unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R)₃,        N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R, SR, NCS, SCN, NCO, or OCN; or its isomer, pharmaceutically        acceptable salt, pharmaceutical product, polymorph, hydrate or        any combination thereof;    -   wherein at least two of Q₁, Q₂ and Q₃ are not hydrogens; or    -   Q₁ and Q₂ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring and Q₃ is        as defined above; or    -   Q₂ and Q₃ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring and Q₁ is        as defined above; and    -   wherein said formed carbocyclic or heterocyclic ring is not        dihydropyridin-2(1H)-one, pyridin-2(1H)-one or 1H-pyrrole.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula III:

wherein

-   -   Z is NO₂ or CN;    -   Y is CF₃, F, I, Br, Cl, or CN;    -   R₂ is hydrogen, C₁-C₁₂-alkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl,        arylalkyl, benzyl, aryl, or C₃-C₇-cycloalkyl    -   Q₁ is substituted or unsubstituted aryl, substituted or        unsubstituted phenyl, substituted or unsubstituted arylalkyl,        CN, or NO₂;    -   Q₂ is hydrogen, substituted or unsubstituted aryl, substituted        or unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted        or unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, or substituted or unsubstituted arylalkyl;    -   Q₃ is hydrogen, substituted or unsubstituted aryl, substituted        or unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted        or unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, or substituted or unsubstituted arylalkyl;    -   wherein at least one of Q₂ and Q₃ is a substituted or        unsubstituted aryl, substituted or unsubstituted phenyl or        substituted or unsubstituted arylalkyl; or    -   Q₂ and Q₃ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring and Q₁ is        as defined above; or its isomer, pharmaceutically acceptable        salt, pharmaceutical product, polymorph, hydrate or any        combination thereof.

In another embodiment, this invention is directed to a selectiveandrogen receptor degrader (SARD) compound represented by the structureof formula III:

wherein

-   -   Z is NO₂ or CN;    -   Y is CF₃, F, I, Br, Cl, or CN;    -   R₂ is hydrogen, C₁-C₁₂-alkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl,        substituted or unsubstituted arylalkyl, substituted or        unsubstituted benzyl, substituted or unsubstituted aryl, or        substituted or unsubstituted C₃-C₇-cycloalkyl;    -   Q₁, Q₂ and Q₃ are each independently selected from hydrogen,        substituted or unsubstituted aryl, substituted or unsubstituted        phenyl, substituted or unsubstituted arylalkyl, F, Cl, Br, I,        CF₃, CN, NO₂, substituted or unsubstituted cycloalkyl, or        substituted or unsubstituted heterocycloalkyl;    -   wherein least one of Q₁, Q₂ and Q₃ is a substituted or        unsubstituted aryl, substituted or unsubstituted arylalkyl, or        substituted or unsubstituted phenyl;    -   or    -   Q₁ and Q₂ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring and Q₃ is        as defined above;    -   or    -   Q₂ and Q₃ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring and Q₁ is        as defined above; and    -   wherein said formed carbocyclic or heterocyclic ring is not        dihydropyridin-2(1H)-one, pyridin-2(1H)-one or 1H-pyrrole; or        its isomer, pharmaceutically acceptable salt, pharmaceutical        product, polymorph, hydrate or any combination thereof.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula IV:

wherein

-   -   T is OH, OR, —NHCOCH₃, or NHCOR;    -   Z is NO₂, CN, COOH, COR, NHCOR or CONHR;    -   Y is CF₃, F, I, Br, Cl, CN, C(R)₃ or Sn(R)₃;    -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,        CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;    -   R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃; Q₁ is hydrogen,        substituted or unsubstituted linear or branched alkyl,        substituted or unsubstituted aryl, substituted or unsubstituted        phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted arylalkyl, C(R)₃, N(R)₂, NHCOCH₃,        NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,        NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R, SO₂R,        SR, NCS, SCN, NCO, or OCN;    -   Q₂ is hydrogen, substituted or unsubstituted linear or branched        alkyl, substituted or unsubstituted aryl, substituted or        unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R)₃,        N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R, SR, NCS, SCN, NCO, or OCN;    -   or    -   Q₁ and Q₂ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring; or its        isomer, pharmaceutically acceptable salt, pharmaceutical        product, polymorph, hydrate or any combination thereof.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula V:

wherein

-   -   T is OH, OR, —NHCOCH₃, or NHCOR;    -   Z is NO₂, CN, COOH, COR, NHCOR or CONHR;    -   Y is CF₃, F, I, Br, Cl, CN, C(R)₃ or Sn(R)₃;    -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,        CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;    -   R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃; and    -   Q₁ is hydrogen, substituted or unsubstituted linear or branched        alkyl, substituted or unsubstituted aryl, substituted or        unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R)₃,        N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R, SR, NCS, SCN, NCO, or OCN; or its isomer, pharmaceutically        acceptable salt, pharmaceutical product, polymorph, hydrate or        any combination thereof.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula VI:

wherein

-   -   T is OH, OR, —NHCOCH₃, or NHCOR;    -   Z is NO₂, CN, COOH, COR, NHCOR or CONHR;    -   Y is CF₃, F, I, Br, Cl, CN, C(R)₃ or Sn(R)₃;    -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,        CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;    -   R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;    -   Q₁ is hydrogen, substituted or unsubstituted linear or branched        alkyl, substituted or unsubstituted aryl, substituted or        unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R)₃,        N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R, SR, NCS, SCN, NCO, or OCN;    -   Q₂ is hydrogen, substituted or unsubstituted linear or branched        alkyl, substituted or unsubstituted aryl, substituted or        unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R)₃,        N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R, SR, NCS, SCN, NCO, or OCN;    -   or    -   Q₁ and Q₂ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring; or its        isomer, pharmaceutically acceptable salt, pharmaceutical        product, polymorph, hydrate or any combination thereof.

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound represented by the structure offormula VII:

wherein

-   -   T is OH, OR, —NHCOCH₃, or NHCOR;    -   Z is NO₂, CN, COOH, COR, NHCOR or CONHR;    -   Y is CF₃, F, I, Br, Cl, CN, C(R)₃ or Sn(R)₃;    -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,        CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;    -   R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃; and    -   Q₁ is hydrogen, substituted or unsubstituted linear or branched        alkyl, substituted or unsubstituted aryl, substituted or        unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R)₃,        N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R, SR, NCS, SCN, NCO, or OCN; or its isomer, pharmaceutically        acceptable salt, pharmaceutical product, polymorph, hydrate or        any combination thereof.

In one embodiment, Q₁ of compound of formulas I-VII, IA-IB, and IIA-IIBis CN. In another embodiment, Q₁ is F. In another embodiment, Q₁ is Cl.In another embodiment, Q₁ is Br. In another embodiment, Q₁ is I. Inanother embodiment, Q₁ is NO₂. In another embodiment, Q₁ is H. Inanother embodiment, Q₁ is phenyl. In another embodiment, Q₁ is aryl. Inanother embodiment, Q₁ is arylalkyl. In another embodiment, thearylalkyl is benzyl. In another embodiment, Q₁ is 4-fluorophenyl.

In one embodiment, Q₁ of compound of formula III is CN. In anotherembodiment, Q₁ is phenyl. In another embodiment, Q₁ is aryl. In anotherembodiment, Q₁ is arylalkyl. In another embodiment, the arylalkyl isbenzyl. In another embodiment, Q₁ is 4-fluorophenyl.

In one embodiment, Q₁ of compound of formulas VI or VII is F. In anotherembodiment, Q₁ is Cl. In another embodiment, Q₁ is Br. In anotherembodiment, Q₁ is I. In another embodiment, Q₁ is NO₂. In anotherembodiment, Q₁ is CN.

In one embodiment, Q₂ of compound of formulas I-IV, IA-IB, IIA-IIB, andVI is CN. In another embodiment, Q₂ is H. In another embodiment, Q₂ isphenyl. In another embodiment, Q₂ is aryl. In another embodiment, Q₂ isarylalkyl. In another embodiment, the arylalkyl is benzyl. In anotherembodiment, Q₂ is 4-fluorophenyl.

In one embodiment, Q₃ of compound of formula I-III, IA-IB, and IIA-IIBis CN. In another embodiment, Q₃ is H. In another embodiment, Q₃ isphenyl. In another embodiment, Q₃ is aryl. In another embodiment, Q₃ isarylalkyl. In another embodiment, the arylalkyl is benzyl. In anotherembodiment, Q₃ is 4-fluorophenyl.

In one embodiment, Q₁ and Q₂ of compound of formulas I-IV, IA-IB,IIA-IIB and VI are joined together to form a substituted orunsubstituted C₅-C₈ carbocyclic or heterocyclic ring. In anotherembodiment, the C₅-C₈ carbocyclic ring is benzene. In anotherembodiment, the C₅-C₈ carbocyclic ring is substituted benzene, whereinthe substitution is one or more groups selected from halogen, haloalkyl,hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino,alkylamino, dialkylamino, carboxy, thio or thioalkyl. In anotherembodiment, Q₁ and Q₂ are —(CH)₄—. In another embodiment, the C₅-C₈heterocyclic ring is piperidine, pyridine, furan, thiophene, pyrrole,pyrrolidine, pyrazine, piperazine or pyrimidine.

In one embodiment, Q₂ and Q₃ of compound of formulas I-III, IA-IB, andIIA-IIB are joined together to form a substituted or unsubstituted C₅-C₈carbocyclic or heterocyclic ring. In another embodiment, the C₅-C₈carbocyclic ring is benzene. In another embodiment, the C₅-C₈carbocyclic ring is substituted benzene, wherein the substitution is oneor more groups selected from halogen, haloalkyl, hydroxy, alkoxycarbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino,dialkylamino, carboxy, thio or thioalkyl. In another embodiment, Q₂ andQ₃ are —(CH)₄—. In another embodiment, the C₅-C₈ heterocyclic ring ispiperidine, pyridine, furan, thiophene, pyrrole, pyrrolidine, pyrazine,piperazine or pyrimidine.

In one embodiment, Q₁ of compound of formulas I-III, IA-IB, and IIA-IIBis CN, Q₂ is phenyl and Q₃ is hydrogen. In another embodiment, Q₁ is CN,Q₂ is hydrogen and Q₃ is phenyl. In another embodiment, Q₁ is CN, and Q₂and Q₃ are joined to form benzene ring (i.e. are —(CH)₄—).

In one embodiment, R₂ of compound of formulas I-III, IA-IB, and IIA-IIBis alkyl. In another embodiment, R₂ is methyl. In another embodiment, R₂is ethyl. In another embodiment, R₂ is propyl. In another embodiment, R₂is isopropyl. In another embodiment, R₂ is pentyl. In anotherembodiment, R₂ is hexyl. In another embodiment, R₂ is C₃-C₇ cycloalkyl.In another embodiment, R₂ is cyclobutyl. In another embodiment, R₂ isbenzyl. In another embodiment, R₂ is methyl-cyclohexyl. In anotherembodiment, R₂ is CO-phenyl. In another embodiment, R₂ is SO₂-phenyl. Inanother embodiment, R₂ is SO₂-phenyl-OCH₃. In another embodiment, R₂ isSO₂-phenyl-F.

In one embodiment, Z of compound of formulas I-VII, IA-IB, and IIA-IIBis CN. In another embodiment, Z is NO₂. In another embodiment, Z isCOOH. In another embodiment, Z is COR. In another embodiment, Z isNHCOR. In another embodiment, Z is CONHR.

In one embodiment, Y of compound of formulas I-VII, IA-IB, and IIA-IIBis CF₃. In another embodiment, Y is F. In another embodiment, Y is I. Inanother embodiment, Y is Br. In another embodiment, Y is Cl. In anotherembodiment, Y is CN. In another embodiment, Y is C(R)₃. In anotherembodiment, Y is Sn(R)₃.

In one embodiment, Z of compound of formulas I-VII, IA-IB, and IIA-IIBis CN and Y is CF₃. In another embodiment, Z is NO₂ and Y is CF₃. Inanother embodiment, Z is NO₂ and Y is halogen. In another embodiment, Zis CN and Y is halogen.

In one embodiment, R₁ of compound of formulas I-II, IA-IB, IIA-IIB andIV-VII is CH₃. In another embodiment, R₁ is CF₃.

In one embodiment, T of compound of formulas I-II, IA-IB, IIA-IIB andIV-VII is OH. In another embodiment, T is OCH₃.

In one embodiment, R of compound of formulas I-II, IA-IB, IIA-IIB andIV-VII is alkyl. In another embodiment, R is haloalkyl. In anotherembodiment, R is dihaloalkyl. In another embodiment, R is trihaloalkyl.In another embodiment, R is CH₂F. In another embodiment, R is CHF₂. Inanother embodiment, R is CF₃. In another embodiment, R is CF₂CF₃. Inanother embodiment, R is aryl. In another embodiment, R is phenyl. Inanother embodiment, R is F. In another embodiment, R is Cl. In anotherembodiment, R is Br. In another embodiment, R is I. In anotherembodiment, R is alkenyl. In another embodiment, R is hydroxyl (OH).

In one embodiment, this invention is directed to a selective androgenreceptor degrader (SARD) compound selected from any one of the followingstructures:

The term “carbocyclic ring” refers to either saturated, unsaturated oraromatic ring composed exclusively of carbon atoms.

The term “heterocycle” group refers, in one embodiment, to a ringstructure comprising in addition to carbon atoms, sulfur, oxygen,nitrogen or any combination thereof, as part of the ring. In anotherembodiment, the heterocycle is a 3-12 membered ring. In anotherembodiment, the heterocycle is a 6 membered ring. In another embodiment,the heterocycle is a 5-7 membered ring. In another embodiment, theheterocycle is a 4-8 membered ring. In another embodiment, theheterocycle group may be unsubstituted or substituted by a halogen,haloalkyl, hydroxyl, alkoxy, carbonyl, amido, alkylamido, dialkylamido,cyano, nitro, CO₂H, amino, alkylamino, dialkylamino, carboxyl, thioand/or thioalkyl. In another embodiment, the heterocycle ring may befused to another saturated or unsaturated cycloalkyl or heterocyclic 3-8membered ring. In another embodiment, the heterocyclic ring is asaturated ring. In another embodiment, the heterocyclic ring is anunsaturated ring. In another embodiment, the heterocycle is piperidine.In another embodiment, the heterocycle is pyridine. In anotherembodiment, the heterocycle is piperidine, pyridine, furan, thiophene,pyrrole, pyrrolidine, pyrazine, piperazine or pyrimidine.

The term “cycloalkyl” refers to a non-aromatic, monocyclic or polycyclicring comprising carbon and hydrogen atoms. A cycloalkyl group can haveone or more carbon-carbon double bonds in the ring so long as the ringis not rendered aromatic by their presence. Examples of cycloalkylgroups include, but are not limited to, (C₃-C₇) cycloalkyl groups, suchas cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl,and saturated cyclic and bicyclic terpenes and (C₃-C₇) cycloalkenylgroups, such as cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, and cycloheptenyl, and unsaturated cyclic and bicyclicterpenes. A cycloalkyl group can be unsubstituted or substituted by oneor two substituents. Preferably, the cycloalkyl group is a monocyclicring or bicyclic ring.

Non limiting examples for “C₅-C₈ carbocyclic or heterocyclic rings” arecarbocyclic rings such as cyclopentane, cyclopentene, cyclohexane,benzene, and cyclohexene rings, and heterocyclic rings such as pyran,dihydropyran, tetrahydropyran, dihydropyrrole, tetrahydropyrrole,pyrazine, dihydropyrazine, tetrahydropyrazine, pyrimidine,dihydropyrimidine, tetrahydropyrimidone, pyrazole, dihydropyrazole,tetrahydropyrazole, piperidine, piperazine, pyridine, dihydropyridine,tetrahydropyridine, morpholine, thiomorpholine, furan, dihydrofuran,tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene,thiazole, imidazole, isoxazole, and the like.

The term “alkyl” refers, in one embodiment, to a saturated aliphatichydrocarbon, including straight-chain, branched-chain and cyclic alkylgroups. In one embodiment, the alkyl group has 1-12 carbons. In anotherembodiment, the alkyl group has 1-7 carbons. In another embodiment, thealkyl group has 1-6 carbons. In another embodiment, the alkyl group has1-4 carbons. In another embodiment, the cyclic alkyl group has 3-8carbons. In another embodiment, the cyclic alkyl group has 3-12 carbons.In another embodiment, the branched alkyl is an alkyl substituted byalkyl side chains of 1 to 5 carbons. In another embodiment, the branchedalkyl is an alkyl substituted by haloalkyl side chains of 1 to 5carbons. The alkyl group may be unsubstituted or substituted by ahalogen, haloalkyl, hydroxyl, alkoxy carbonyl, amido, alkylamido,dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thioand/or thioalkyl.

An “arylalkyl” group refers to an alkyl bound to an aryl, wherein alkyland aryl are as defined above. An example of an arylalkyl group is abenzyl group.

An “alkenyl” group refers, in another embodiment, to an unsaturatedhydrocarbon, including straight chain, branched chain and cyclic groupshaving one or more double bonds. The alkenyl group may have one doublebond, two double bonds, three double bonds, etc. In another embodiment,the alkenyl group has 2-12 carbons. In another embodiment, the alkenylgroup has 2-6 carbons. In another embodiment, the alkenyl group has 2-4carbons. Examples of alkenyl groups are ethenyl, propenyl, butenyl,cyclohexenyl, etc. The alkenyl group may be unsubstituted or substitutedby a halogen, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido,nitro, amino, alkylamino, dialkylamino, carboxyl, thio and/or thioalkyl.

An “aryl” group refers to an aromatic group having at least onecarbocyclic aromatic group or heterocyclic aromatic group, which may beunsubstituted or substituted by one or more groups selected fromhalogen, haloalkyl, hydroxy, alkoxy carbonyl, amido, alkylamido,dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxy or thio orthioalkyl. Nonlimiting examples of aryl rings are phenyl, naphthyl,pyranyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridinyl,furanyl, thiophenyl, thiazolyl, imidazolyl, isoxazolyl, and the like. Inone embodiment, the aryl group is a 4-8 membered ring. In anotherembodiment, the aryl group is a 4-12 membered ring(s). In anotherembodiment, the aryl group is a 6 membered ring. In another embodiment,the aryl group is a 5 membered ring. In another embodiment, the arylgroup is 2-4 fused ring system.

A “aldehyde” group refers, in one embodiment, to an alkyl, or alkenylsubstituted by a formyl group, wherein the alkyl or alkenyl are asdefined hereinabove. In another embodiment, the aldehyde group is anaryl, or phenyl group substituted by a formyl group, wherein the aryl isas defined hereinabove. Examples of aldehydes are: formyl, acetal,propanal, butanal, pentanal, benzaldehyde. In another embodiment, thealdehyde group is a formyl group.

A “haloalkyl” group refers, in another embodiment, to an alkyl group asdefined above, which is substituted by one or more halogen atoms, e.g.by F, Cl, Br or I.

A “hydroxyl” group refers, in another embodiment, to an OH group. It isunderstood by a person skilled in the art that when R₁, R₂ or R₃ in thecompounds of the present invention is OR, then R is not OH.

In one embodiment, the term “halogen” or “halo” refers to a halogen,such as F, Cl, Br or I.

In another embodiment, the phrase “phenol” refers to an alcohol (OH)derivative of benzene.

In one embodiment, this invention provides for the use of a compound asherein described and/or, its derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, prodrug, polymorph, crystal or combinations thereof.

In one embodiment, the methods of this invention make use of“pharmaceutically acceptable salts” of the compounds, which may beproduced, by reaction of a compound of this invention with an acid orbase.

Suitable pharmaceutically acceptable salts of amines of the compounds ofthe methods of this invention may be prepared from an inorganic acid orfrom an organic acid. In one embodiment, examples of inorganic salts ofamines are bisulfates, borates, bromides, chlorides, hemisulfates,hydrobromates, hydrochlorates, 2-hydroxyethylsulfonates(hydroxyethanesulfonates), iodates, iodides, isothionates, nitrates,persulfates, phosphate, sulfates, sulfamates, sulfanilates, sulfonicacids (alkylsulfonates, arylsulfonates, halogen substitutedalkylsulfonates, halogen substituted arylsulfonates), sulfonates andthiocyanates.

In one embodiment, examples of organic salts of amines may be selectedfrom aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, examples of which areacetates, arginines, aspartates, ascorbates, adipates, anthranilates,algenates, alkane carboxylates, substituted alkane carboxylates,alginates, benzenesulfonates, benzoates, bisulfates, butyrates,bicarbonates, bitartrates, carboxylates, citrates, camphorates,camphorsulfonates, cyclohexylsulfamates, cyclopentanepropionates,calcium edetates, camsylates, carbonates, clavulanates, cinnamates,dicarboxylates, digluconates, dodecylsulfonates, dihydrochlorides,decanoates, enanthuates, ethanesulfonates, edetates, edisylates,estolates, esylates, fumarates, formates, fluorides, galacturonates,gluconates, glutamates, glycolates, glucorates, glucoheptanoates,glycerophosphates, gluceptates, glycollylarsanilates, glutarates,glutamates, heptanoates, hexanoates, hydroxymaleates, hydroxycarboxlicacids, hexylresorcinates, hydroxybenzoates, hydroxynaphthoates,hydrofluorates, lactates, lactobionates, laurates, malates, maleates,methylenebis(beta-oxynaphthoate), malonates, mandelates, mesylates,methane sulfonates, methylbromides, methylnitrates, methylsulfonates,monopotassium maleates, mucates, monocarboxylates, nitrates,naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates, napsylates,N-methylglucamines, oxalates, octanoates, oleates, pamoates,phenylacetates, picrates, phenylbenzoates, pivalates, propionates,phthalates, pectinates, phenylpropionates, palmitates, pantothenates,polygalacturates, pyruvates, quinates, salicylates, succinates,stearates, sulfanilates, subacetates, tartarates, theophyllineacetates,p-toluenesulfonates (tosylates), trifluoroacetates, terephthalates,tannates, teoclates, trihaloacetates, triethiodide, tricarboxylates,undecanoates and valerates.

In one embodiment, examples of inorganic salts of carboxylic acids orphenols may be selected from ammonium, alkali metals to include lithium,sodium, potassium, cesium; alkaline earth metals to include calcium,magnesium, aluminium; zinc, barium, cholines, quaternary ammoniums.

In another embodiment, examples of organic salts of carboxylic acids orphenols may be selected from arginine, organic amines to includealiphatic organic amines, alicyclic organic amines, aromatic organicamines, benzathines, t-butylamines, benethamines(N-benzylphenethylamine), dicyclohexylamines, dimethylamines,diethanolamines, ethanolamines, ethylenediamines, hydrabamines,imidazoles, lysines, methylamines, meglamines, N-methyl-D-glucamines,N,N′-dibenzylethylenediamines, nicotinamides, organic amines,ornithines, pyridines, picolies, piperazines, procaine,tris(hydroxymethyl)methylamines, triethylamines, triethanolamines,trimethylamines, tromethamines and ureas.

In one embodiment, the salts may be formed by conventional means, suchas by reacting the free base or free acid form of the product with oneor more equivalents of the appropriate acid or base in a solvent ormedium in which the salt is insoluble or in a solvent such as water,which is removed in vacuo or by freeze drying or by exchanging the ionsof an existing salt for another ion or suitable ion-exchange resin.

In one embodiment, the methods of this invention make use of apharmaceutically acceptable salt of the compounds of this invention. Inone embodiment, the methods of this invention make use of apharmaceutically acceptable salt of compounds of formulas I-VII, IA-IB,and IIA-IIB. In one embodiment, the methods of this invention make useof a salt of an amine of the compounds of formulas I-VII, IA-IB, andIIA-IIB of this invention. In one embodiment, the methods of thisinvention make use of a salt of a phenol of the compounds of formulasI-VII, IA-IB, and IIA-IIB of this invention.

In one embodiment, the methods of this invention make use of a freebase, free acid, non-charged or non-complexed compounds of formulasI-VII, IA-IB, and IIA-IIB and/or its isomer, pharmaceutical product,hydrate, polymorph, or combinations thereof.

In one embodiment, the methods of this invention make use of an isomerof a compound of formulas I-VII, IA-IB, and IIA-IIB. In one embodiment,the methods of this invention make use of a pharmaceutical product of acompound of formulas I-VII, IA-IB, and IIA-IIB. In one embodiment, themethods of this invention make use of a hydrate of a compound offormulas I-VII, IA-IB, and IIA-IIB. In one embodiment, the methods ofthis invention make use of a polymorph of a compound of formulas I-VII,IA-IB, and IIA-IIB. In one embodiment, the methods of this inventionmake use of a metabolite of a compound of formulas I-VII, IA-IB, andIIA-IIB. In another embodiment, the methods of this invention make useof a composition comprising a compound of formulas I-VII, IA-IB, andIIA-IIB, as described herein, or, in another embodiment, a combinationof isomer, metabolite, pharmaceutical product, hydrate, polymorph of acompound of formulas I-VII, IA-IB, and IIA-IIB.

In one embodiment, the term “isomer” includes, but is not limited to,optical isomers and analogs, structural isomers and analogs,conformational isomers and analogs, and the like.

In one embodiment, the term “isomer” is meant to encompass opticalisomers of the SARD compound. It will be appreciated by those skilled inthe art that the SARDs of the present invention contain at least onechiral center. Accordingly, the SARDs used in the methods of the presentinvention may exist in, and be isolated in, optically-active or racemicforms. Some compounds may also exhibit polymorphism. It is to beunderstood that the present invention encompasses any racemic,optically-active, polymorphic, or stereroisomeric form, or mixturesthereof, which form possesses properties useful in the treatment ofandrogen-related conditions described herein. In one embodiment, theSARDs are the pure (R)-isomers. In another embodiment, the SARDs are thepure (S)-isomers. In another embodiment, the SARDs are a mixture of the(R) and the (S) isomers. In another embodiment, the SARDs are a racemicmixture comprising an equal amount of the (R) and the (S) isomers. It iswell known in the art how to prepare optically-active forms (forexample, by resolution of the racemic form by recrystallizationtechniques, by synthesis from optically-active starting materials, bychiral synthesis, or by chromatographic separation using a chiralstationary phase).

In another embodiment, this invention further includes hydrates of thecompounds. The invention also includes use of N-oxides of the aminosubstituents of the compounds described herein.

In one embodiment, the term “hydrate” refers to hemihydrate,monohydrate, dihydrate, trihydrate or others, as known in the art.

This invention provides, in other embodiments, use of metabolites of thecompounds as herein described. In one embodiment, “metabolite” means anysubstance produced from another substance by metabolism or a metabolicprocess.

In one embodiment, the compounds of the invention can also include allisotopes of atoms occurring in the intermediates or final compounds.Isotopes include those atoms having the same atomic number but differentmass numbers. In one embodiment, the compound is isotopically labelledwith an isotope selected from the group consisting of ²H, ³H, ¹³C, ¹⁴C,and ¹⁸F. In one embodiment, the compound is isotopically labelled withan isotope of ²H or ³H. In one embodiment, the compound is isotopicallylabelled with an isotope of ¹³C or ¹⁴C. In another embodiment, thecompound is isotopically labelled with an isotope of ¹⁸F.

Compounds as herein described may be prepared by any means known in theart, including inter alia, those described in U.S. patent applicationSer. No. 11/505,363, U.S. patent application Ser. No. 11/505,499 andU.S. patent application Ser. No. 11/394,181; and U.S. patent applicationSer. No. 10/462,837 fully incorporated by reference herein in theirentirety.

In another example, Compounds 13-21, 17a, 49 or 50 are preparedaccording to Example 1A and Example 1B.

Biological Activity of Selective Androgen Receptor Degraders

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of prostate cancer (PCa) and its symptoms, orincreasing the survival of a male subject suffering from prostate cancercomprising administering to said subject a therapeutically effectiveamount of a compound or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof,represented by a compound of formula I:

wherein

-   -   T is OH, OR, —NHCOCH₃, or NHCOR;    -   Z is NO₂, CN, COOH, COR, NHCOR or CONHR;    -   Y is CF₃, F, I, Br, Cl, CN, C(R)₃ or Sn(R)₃;    -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,        CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;    -   R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;    -   R₂ is hydrogen, C₁-C₁₂-alkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl,        arylalkyl, benzyl, aryl, or C₃-C₇-cycloalkyl;    -   Q₁, Q₂, Q₃, Q₄, and Q₅ are each independently selected from        hydrogen, substituted or unsubstituted linear or branched alkyl,        substituted or unsubstituted aryl, substituted or unsubstituted        phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted arylalkyl, C(R)₃, N(R)₂, NHCOCH₃,        NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,        NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R, SO₂R,        SR, NCS, SCN, NCO, or OCN;    -   or its isomer, pharmaceutically acceptable salt, pharmaceutical        product, polymorph, hydrate or any combination thereof wherein        at least two of Q₁, Q₂, Q₃, Q₄, and Q₅ are not hydrogens; or    -   Q₁ and Q₂ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring, and Q₃,        Q₄, and Q₅ are as defined above; or    -   Q₂ and Q₃ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring, and Q₁,        Q₄, and Q₅ are as defined above; and    -   wherein said formed carbocyclic or heterocyclic ring is not        dihydropyridin-2(1H)-one, pyridin-2(1H)-one or 1H-pyrrole.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of prostate cancer (PCa) and its symptoms, orincreasing the survival of a male subject suffering from prostate cancercomprising administering to said subject a therapeutically effectiveamount of a compound or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof,represented by a compound of formula IA:

wherein

-   -   T is OH, OR, —NHCOCH₃, or NHCOR;    -   Z is NO₂, CN, COOH, COR, NHCOR or CONHR;    -   Y is CF₃, F, I, Br, Cl, CN, C(R)₃ or Sn(R)₃;    -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,        CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;    -   R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;    -   R₂ is hydrogen, C₁-C₁₂-alkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl,        arylalkyl, benzyl, aryl, or C₃-C₇-cycloalkyl;    -   Q₁, Q₂, Q₃, Q₄, and Q₅ are each independently selected from        hydrogen, substituted or unsubstituted linear or branched alkyl,        substituted or unsubstituted aryl, substituted or unsubstituted        phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted arylalkyl, C(R)₃, N(R)₂, NHCOCH₃,        NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,        NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R, SO₂R,        SR, NCS, SCN, NCO, or OCN; or its isomer, pharmaceutically        acceptable salt, pharmaceutical product, polymorph, hydrate or        any combination thereof;    -   wherein at least two of Q₁, Q₂, Q₃, Q₄, and Q₅ are not        hydrogens; or    -   Q₁ and Q₂ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring, and Q₃,        Q₄, and Q₅ are as defined above; or    -   Q₂ and Q₃ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring, and Q₁,        Q₄, and Q₅ are as defined above; and    -   wherein said formed carbocyclic or heterocyclic ring is not        dihydropyridin-2(1H)-one, pyridin-2(1H)-one or 1H-pyrrole.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of prostate cancer (PCa) and its symptoms, orincreasing the survival of a male subject suffering from prostate cancercomprising administering to said subject a therapeutically effectiveamount of a compound or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof,represented by a compound of formula IB:

wherein

-   -   T is OH, OR, —NHCOCH₃, or NHCOR;    -   Z is NO₂, CN, COOH, COR, NHCOR or CONHR;    -   Y is CF₃, F, I, Br, Cl, CN, C(R)₃ or Sn(R)₃;    -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,        CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;    -   R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;    -   R₂ is hydrogen, C₁-C₁₂-alkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl,        arylalkyl, benzyl, aryl, or C₃-C₇-cycloalkyl;    -   Q₁, Q₂, Q₃, Q₄, and Q₅ are each independently selected from        hydrogen, substituted or unsubstituted linear or branched alkyl,        substituted or unsubstituted aryl, substituted or unsubstituted        phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted arylalkyl, C(R)₃, N(R)₂, NHCOCH₃,        NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,        NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R, SO₂R,        SR, NCS, SCN, NCO, or OCN; or its isomer, pharmaceutically        acceptable salt, pharmaceutical product, polymorph, hydrate or        any combination thereof;    -   wherein at least two of Q₁, Q₂, Q₃, Q₄, and Q₅ are not        hydrogens; or    -   Q₁ and Q₂ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring, and Q₃,        Q₄, and Q₅ are as defined above; or    -   Q₂ and Q₃ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring, and Q₁,        Q₄, and Q₅ are as defined above; and    -   wherein said formed carbocyclic or heterocyclic ring is not        dihydropyridin-2(1H)-one, pyridin-2(1H)-one or 1H-pyrrole.

In another embodiment, the prostate cancer is advanced prostate cancer,castration resistant prostate cancer (CRPC), metastatic CRPC (mCRPC),non-metastatic CRPC (nmCRPC), high-risk nmCRPC or any combinationthereof. In another embodiment, the prostate cancer depends on AR-FLand/or AR-SV for proliferation. In another embodiment, the subjectfurther receives androgen deprivation therapy (ADT). In anotherembodiment, the subject has failed androgen deprivation therapy (ADT).In another embodiment, the cancer is resistant to treatment with anandrogen receptor antagonist. In another embodiment, the cancer isresistant to treatment with enzalutamide, bicalutamide, abiraterone,ARN-509, AZD-3514, galeterone, ASC-J9, flutamide, hydroxyflutamide,nilutamide, cyproterone acetate, ketoconazole, spironolactone, or anycombination thereof. In another embodiment, administering the compoundto a subject reduces the levels of AR, AR-full length (AR-FL), AR-FLwith antiandrogen resistance-conferring AR-LBD mutations, AR-splicevariant (AR-SV), gene-amplified AR, or any combination thereof, in saidsubject.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of prostate cancer (PCa) and its symptoms, orincreasing the survival of a male subject suffering from prostate cancercomprising administering to said subject a therapeutically effectiveamount of a compound or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof,represented by a compound of formula II:

wherein

-   -   T is OH, OR, —NHCOCH₃, or NHCOR;    -   Z is NO₂, CN, COOH, COR, NHCOR or CONHR;    -   Y is CF₃, F, I, Br, Cl, CN, C(R)₃ or Sn(R)₃;    -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,        CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;    -   R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;    -   R₂ is hydrogen, C₁-C₁₂-alkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl,        arylalkyl, benzyl, aryl, or C₃-C₇-cycloalkyl;    -   Q₁ is hydrogen, substituted or unsubstituted linear or branched        alkyl, substituted or unsubstituted aryl, substituted or        unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R)₃,        N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R, SR, NCS, SCN, NCO, or OCN;    -   Q₂ is hydrogen, substituted or unsubstituted linear or branched        alkyl, substituted or unsubstituted aryl, substituted or        unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R)₃,        N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R, SR, NCS, SCN, NCO, or OCN;    -   Q₃ is hydrogen, substituted or unsubstituted linear or branched        alkyl, substituted or unsubstituted aryl, substituted or        unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R)₃,        N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R, SR, NCS, SCN, NCO, or OCN; or its isomer, pharmaceutically        acceptable salt, pharmaceutical product, polymorph, hydrate or        any combination thereof;    -   wherein least two of Q₁, Q₂ and Q₃ are not hydrogens; or    -   Q₁ and Q₂ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring and Q₃ is        as defined above; or    -   Q₂ and Q₃ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring and Q₁ is        as defined above; and    -   wherein said formed carbocyclic or heterocyclic ring is not        dihydropyridin-2(1H)-one, pyridin-2(1H)-one or 1H-pyrrole.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of prostate cancer (PCa) and its symptoms, orincreasing the survival of a male subject suffering from prostate cancercomprising administering to said subject a therapeutically effectiveamount of a compound or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof,represented by a compound of formula IIA:

wherein

-   -   T is OH, OR, —NHCOCH₃, or NHCOR;    -   Z is NO₂, CN, COOH, COR, NHCOR or CONHR;    -   Y is CF₃, F, I, Br, Cl, CN, C(R)₃ or Sn(R)₃;    -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,        CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;    -   R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;    -   R₂ is hydrogen, C₁-C₁₂-alkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl,        arylalkyl, benzyl, aryl, or C₃-C₇-cycloalkyl;    -   Q₁ is hydrogen, substituted or unsubstituted linear or branched        alkyl, substituted or unsubstituted aryl, substituted or        unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R)₃,        N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R, SR, NCS, SCN, NCO, or OCN;    -   Q₂ is hydrogen, substituted or unsubstituted linear or branched        alkyl, substituted or unsubstituted aryl, substituted or        unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R)₃,        N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R, SR, NCS, SCN, NCO, or OCN;    -   Q₃ is hydrogen, substituted or unsubstituted linear or branched        alkyl, substituted or unsubstituted aryl, substituted or        unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R)₃,        N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R, SR, NCS, SCN, NCO, or OCN; or its isomer, pharmaceutically        acceptable salt, pharmaceutical product, polymorph, hydrate or        any combination thereof;    -   wherein least two of Q₁, Q₂ and Q₃ are not hydrogens; or    -   Q₁ and Q₂ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring and Q₃ is        as defined above; or    -   Q₂ and Q₃ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring and Q₁ is        as defined above; and    -   wherein said formed carbocyclic or heterocyclic ring is not        dihydropyridin-2(1H)-one, pyridin-2(1H)-one or 1H-pyrrole.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of prostate cancer (PCa) and its symptoms, orincreasing the survival of a male subject suffering from prostate cancercomprising administering to said subject a therapeutically effectiveamount of a compound or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof,represented by a compound of formula IIB:

wherein

-   -   T is OH, OR, —NHCOCH₃, or NHCOR;    -   Z is NO₂, CN, COOH, COR, NHCOR or CONHR;    -   Y is CF₃, F, I, Br, Cl, CN, C(R)₃ or Sn(R)₃;    -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,        CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;    -   R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;    -   R₂ is hydrogen, C₁-C₁₂-alkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl,        arylalkyl, benzyl, aryl, or C₃-C₇-cycloalkyl;    -   Q₁ is hydrogen, substituted or unsubstituted linear or branched        alkyl, substituted or unsubstituted aryl, substituted or        unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R)₃,        N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R, SR, NCS, SCN, NCO, or OCN;    -   Q₂ is hydrogen, substituted or unsubstituted linear or branched        alkyl, substituted or unsubstituted aryl, substituted or        unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R)₃,        N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R, SR, NCS, SCN, NCO, or OCN;    -   Q₃ is hydrogen, substituted or unsubstituted linear or branched        alkyl, substituted or unsubstituted aryl, substituted or        unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R)₃,        N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R, SR, NCS, SCN, NCO, or OCN; or its isomer, pharmaceutically        acceptable salt, pharmaceutical product, polymorph, hydrate or        any combination thereof;    -   wherein at least two of Q₁, Q₂ and Q₃ are not hydrogens; or    -   Q₁ and Q₂ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring and Q₃ is        as defined above; or    -   Q₂ and Q₃ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring and Q₁ is        as defined above; and

wherein said formed carbocyclic or heterocyclic ring is notdihydropyridin-2(1H)-one, pyridin-2(1H)-one or 1H-pyrrole.

In another embodiment, the prostate cancer is advanced prostate cancer,castration resistant prostate cancer (CRPC), metastatic CRPC (mCRPC),non-metastatic CRPC (nmCRPC), high-risk nmCRPC or any combinationthereof. In another embodiment, the prostate cancer depends on AR-FLand/or AR-SV for proliferation. In another embodiment, the subjectfurther receives androgen deprivation therapy (ADT). In anotherembodiment, the subject has failed androgen deprivation therapy (ADT).In another embodiment, the cancer is resistant to treatment with anandrogen receptor antagonist. In another embodiment, the cancer isresistant to treatment with enzalutamide, bicalutamide, abiraterone,ARN-509, AZD-3514, galeterone, ASC-J9, flutamide, hydroxyflutamide,nilutamide, cyproterone acetate, ketoconazole, spironolactone, or anycombination thereof. In another embodiment, administering the compoundto a subject reduces the levels of AR, AR-full length (AR-FL), AR-FLwith antiandrogen resistance-conferring AR-LBD mutations, AR-splicevariant (AR-SV), gene-amplified AR, or any combination thereof, in saidsubject.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of prostate cancer (PCa) and its symptoms, orincreasing the survival of a male subject suffering from prostate cancercomprising administering to said subject a therapeutically effectiveamount of a compound or its isomer, pharmaceutical product,pharmaceutically acceptable salt, polymorph, hydrate or any combinationthereof, represented by a compound of formula III:

wherein

-   -   Z is NO₂ or CN;    -   Y is CF₃, F, I, Br, Cl, or CN;    -   R₂ is hydrogen, C₁-C₁₂-alkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl,        arylalkyl, benzyl, aryl, or C₃-C₇-cycloalkyl    -   Q₁ is substituted or unsubstituted aryl, substituted or        unsubstituted phenyl, substituted or unsubstituted arylalkyl,        CN, or NO₂;    -   Q₂ is hydrogen, substituted or unsubstituted aryl, substituted        or unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted        or unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, or substituted or unsubstituted arylalkyl;    -   Q₃ is hydrogen, substituted or unsubstituted aryl, substituted        or unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted        or unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, or substituted or unsubstituted arylalkyl;    -   wherein at least one of Q₂ and Q₃ is a substituted or        unsubstituted aryl, substituted or unsubstituted phenyl, or        substituted or unsubstituted arylalkyl; or    -   Q₂ and Q₃ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring and Q₁ is        as defined above.

In another embodiment, the prostate cancer is advanced prostate cancer,castration resistant prostate cancer (CRPC), metastatic CRPC (mCRPC),non-metastatic CRPC (nmCRPC), high-risk nmCRPC or any combinationthereof. In another embodiment, the prostate cancer depends on AR-FLand/or AR-SV for proliferation. In another embodiment, the subjectfurther receives androgen deprivation therapy (ADT). In anotherembodiment, the subject has failed androgen deprivation therapy (ADT).In another embodiment, the cancer is resistant to treatment with anandrogen receptor antagonist. In another embodiment, the cancer isresistant to treatment with enzalutamide, bicalutamide, abiraterone,ARN-509, AZD-3514, galeterone, ASC-J9, flutamide, hydroxyflutamide,nilutamide, cyproterone acetate, ketoconazole, spironolactone, or anycombination thereof. In another embodiment, administering the compoundto a subject reduces the levels of AR, AR-full length (AR-FL), AR-FLwith antiandrogen resistance-conferring AR-LBD mutations, AR-splicevariant (AR-SV), gene-amplified AR, or any combination thereof, in saidsubject.

In another embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of prostate cancer (PCa) and its symptoms, orincreasing the survival of a male subject suffering from prostate cancercomprising administering to said subject a therapeutically effectiveamount of a compound or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof,represented by a compound of formula III:

wherein

-   -   Z is NO₂ or CN;    -   Y is CF₃, F, I, Br, Cl, or CN;    -   R₂ is hydrogen, C₁-C₁₂-alkyl, —SO₂-aryl, —SO₂-phenyl, —CO-aryl,        substituted or unsubstituted arylalkyl, substituted or        unsubstituted benzyl, substituted or unsubstituted aryl, or        substituted or unsubstituted C₃-C₇-cycloalkyl;    -   Q₁, Q₂ and Q₃ are each independently selected from hydrogen,        substituted or unsubstituted aryl, substituted or unsubstituted        phenyl, substituted or unsubstituted arylalkyl, F, Cl, Br, I,        CF₃, CN, NO₂, substituted or unsubstituted cycloalkyl, or        substituted or unsubstituted heterocycloalkyl;    -   wherein at least one of Q₁, Q₂ and Q₃ is a substituted or        unsubstituted aryl, substituted or unsubstituted arylalkyl, or        substituted or unsubstituted phenyl;    -   or    -   Q₁ and Q₂ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring and Q₃ is        as defined above;    -   or    -   Q₂ and Q₃ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring and Q₁ is        as defined above; and    -   wherein said formed carbocyclic or heterocyclic ring is not        dihydropyridin-2(1H)-one, pyridin-2(1H)-one or 1H-pyrrole.

In another embodiment, the prostate cancer is advanced prostate cancer,castration resistant prostate cancer (CRPC), metastatic CRPC (mCRPC),non-metastatic CRPC (nmCRPC), high-risk nmCRPC or any combinationthereof. In another embodiment, the prostate cancer depends on AR-FLand/or AR-SV for proliferation. In another embodiment, the subjectfurther receives androgen deprivation therapy (ADT). In anotherembodiment, the subject has failed androgen deprivation therapy (ADT).In another embodiment, the cancer is resistant to treatment with anandrogen receptor antagonist. In another embodiment, the cancer isresistant to treatment with enzalutamide, bicalutamide, abiraterone,ARN-509, AZD-3514, galeterone, ASC-J9, flutamide, hydroxyflutamide,nilutamide, cyproterone acetate, ketoconazole, spironolactone, or anycombination thereof. In another embodiment, administering the compoundto a subject reduces the levels of AR, AR-full length (AR-FL), AR-FLwith antiandrogen resistance-conferring AR-LBD mutations, AR-splicevariant (AR-SV), gene-amplified AR, or any combination thereof, in saidsubject.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of prostate cancer (PCa) and its symptoms, orincreasing the survival of a male subject suffering from prostate cancercomprising administering to said subject a therapeutically effectiveamount of a compound or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof,represented by a compound of formula IV:

wherein

-   -   T is OH, OR, —NHCOCH₃, or NHCOR;    -   Z is NO₂, CN, COOH, COR, NHCOR or CONHR;    -   Y is CF₃, F, I, Br, Cl, CN, C(R)₃ or Sn(R)₃;    -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,        CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;    -   R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;    -   Q₁ is hydrogen, substituted or unsubstituted linear or branched        alkyl, substituted or unsubstituted aryl, substituted or        unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R)₃,        N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R, SR, NCS, SCN, NCO, or OCN;    -   Q₂ is hydrogen, substituted or unsubstituted linear or branched        alkyl, substituted or unsubstituted aryl, substituted or        unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R)₃,        N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R, SR, NCS, SCN, NCO, or OCN;    -   or    -   Q₁ and Q₂ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring.

In another embodiment, the prostate cancer is advanced prostate cancer,castration resistant prostate cancer (CRPC), metastatic CRPC (mCRPC),non-metastatic CRPC (nmCRPC), high-risk nmCRPC or any combinationthereof. In another embodiment, the prostate cancer depends on AR-FLand/or AR-SV for proliferation. In another embodiment, the subjectfurther receives androgen deprivation therapy (ADT). In anotherembodiment, the subject has failed androgen deprivation therapy (ADT).In another embodiment, the cancer is resistant to treatment with anandrogen receptor antagonist. In another embodiment, the cancer isresistant to treatment with enzalutamide, bicalutamide, abiraterone,ARN-509, AZD-3514, galeterone, ASC-J9, flutamide, hydroxyflutamide,nilutamide, cyproterone acetate, ketoconazole, spironolactone, or anycombination thereof. In another embodiment, administering the compoundto a subject reduces the levels of AR, AR-full length (AR-FL), AR-FLwith antiandrogen resistance-conferring AR-LBD mutations, AR-splicevariant (AR-SV), gene-amplified AR, or any combination thereof, in saidsubject.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of prostate cancer (PCa) and its symptoms, orincreasing the survival of a male subject suffering from prostate cancercomprising administering to said subject a therapeutically effectiveamount of a compound or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof,represented by a compound of formula V:

wherein

-   -   T is OH, OR, —NHCOCH₃, or NHCOR;    -   Z is NO₂, CN, COOH, COR, NHCOR or CONHR;    -   Y is CF₃, F, I, Br, Cl, CN, C(R)₃ or Sn(R)₃;    -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,        CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;    -   R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃; and    -   Q₁ is hydrogen, substituted or unsubstituted linear or branched        alkyl, substituted or unsubstituted aryl, substituted or        unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R)₃,        N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R, SR, NCS, SCN, NCO, or OCN.

In another embodiment, the prostate cancer is advanced prostate cancer,castration resistant prostate cancer (CRPC), metastatic CRPC (mCRPC),non-metastatic CRPC (nmCRPC), high-risk nmCRPC or any combinationthereof. In another embodiment, the prostate cancer depends on AR-FLand/or AR-SV for proliferation. In another embodiment, the subjectfurther receives androgen deprivation therapy (ADT). In anotherembodiment, the subject has failed androgen deprivation therapy (ADT).In another embodiment, the cancer is resistant to treatment with anandrogen receptor antagonist. In another embodiment, the cancer isresistant to treatment with enzalutamide, bicalutamide, abiraterone,ARN-509, AZD-3514, galeterone, ASC-J9, flutamide, hydroxyflutamide,nilutamide, cyproterone acetate, ketoconazole, spironolactone, or anycombination thereof. In another embodiment, administering the compoundto a subject reduces the levels of AR, AR-full length (AR-FL), AR-FLwith antiandrogen resistance-conferring AR-LBD mutations, AR-splicevariant (AR-SV), gene-amplified AR, or any combination thereof, in saidsubject.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of prostate cancer (PCa) and its symptoms, orincreasing the survival of a male subject suffering from prostate cancercomprising administering to said subject a therapeutically effectiveamount of a compound or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof,represented by a compound of formula VI:

wherein

-   -   T is OH, OR, —NHCOCH₃, or NHCOR;    -   Z is NO₂, CN, COOH, COR, NHCOR or CONHR;    -   Y is CF₃, F, I, Br, Cl, CN, C(R)₃ or Sn(R)₃;    -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,        CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;    -   R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;    -   Q₁ is hydrogen, substituted or unsubstituted linear or branched        alkyl, substituted or unsubstituted aryl, substituted or        unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R)₃,        N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R, SR, NCS, SCN, NCO, or OCN;    -   Q₂ is hydrogen, substituted or unsubstituted linear or branched        alkyl, substituted or unsubstituted aryl, substituted or        unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R)₃,        N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R, SR, NCS, SCN, NCO, or OCN;    -   or    -   Q₁ and Q₂ are joined together to form a substituted or        unsubstituted C₅-C₈ carbocyclic or heterocyclic ring.

In another embodiment, the prostate cancer is advanced prostate cancer,castration resistant prostate cancer (CRPC), metastatic CRPC (mCRPC),non-metastatic CRPC (nmCRPC), high-risk nmCRPC or any combinationthereof. In another embodiment, the prostate cancer depends on AR-FLand/or AR-SV for proliferation. In another embodiment, the subjectfurther receives androgen deprivation therapy (ADT). In anotherembodiment, the subject has failed androgen deprivation therapy (ADT).In another embodiment, the cancer is resistant to treatment with anandrogen receptor antagonist. In another embodiment, the cancer isresistant to treatment with enzalutamide, bicalutamide, abiraterone,ARN-509, AZD-3514, galeterone, ASC-J9, flutamide, hydroxyflutamide,nilutamide, cyproterone acetate, ketoconazole, spironolactone, or anycombination thereof. In another embodiment, administering the compoundto a subject reduces the levels of AR, AR-full length (AR-FL), AR-FLwith antiandrogen resistance-conferring AR-LBD mutations, AR-splicevariant (AR-SV), gene-amplified AR, or any combination thereof, in saidsubject.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of prostate cancer (PCa) and its symptoms, orincreasing the survival of a male subject suffering from prostate cancercomprising administering to said subject a therapeutically effectiveamount of a compound or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof,represented by a compound of formula VII:

wherein

-   -   T is OH, OR, —NHCOCH₃, or NHCOR;    -   Z is NO₂, CN, COOH, COR, NHCOR or CONHR;    -   Y is CF₃, F, I, Br, Cl, CN, C(R)₃ or Sn(R)₃;    -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,        CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;    -   R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃; and    -   Q₁ is hydrogen, substituted or unsubstituted linear or branched        alkyl, substituted or unsubstituted aryl, substituted or        unsubstituted phenyl, F, Cl, Br, I, CF₃, CN, NO₂, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R)₃,        N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R, SR, NCS, SCN, NCO, or OCN.

In another embodiment, the prostate cancer is advanced prostate cancer,castration resistant prostate cancer (CRPC), metastatic CRPC (mCRPC),non-metastatic CRPC (nmCRPC), high-risk nmCRPC or any combinationthereof. In another embodiment, the prostate cancer depends on AR-FLand/or AR-SV for proliferation. In another embodiment, the subjectfurther receives androgen deprivation therapy (ADT). In anotherembodiment, the subject has failed androgen deprivation therapy (ADT).In another embodiment, the cancer is resistant to treatment with anandrogen receptor antagonist. In another embodiment, the cancer isresistant to treatment with enzalutamide, bicalutamide, abiraterone,ARN-509, AZD-3514, galeterone, ASC-J9, flutamide, hydroxyflutamide,nilutamide, cyproterone acetate, ketoconazole, spironolactone, or anycombination thereof. In another embodiment, administering the compoundto a subject reduces the levels of AR, AR-full length (AR-FL), AR-FLwith antiandrogen resistance-conferring AR-LBD mutations, AR-splicevariant (AR-SV), gene-amplified AR, or any combination thereof, in saidsubject.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of prostate cancer (PCa) and its symptoms, orincreasing the survival of a male subject suffering from prostate cancercomprising administering to said subject a therapeutically effectiveamount of a compound or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof,selected from any one of the following structures:

In another embodiment, the prostate cancer is advanced prostate cancer,castration resistant prostate cancer (CRPC), metastatic CRPC (mCRPC),non-metastatic CRPC (nmCRPC), high-risk nmCRPC or any combinationthereof. In another embodiment, the prostate cancer depends on AR-FLand/or AR-SV for proliferation. In another embodiment, the subjectfurther receives androgen deprivation therapy (ADT). In anotherembodiment, the subject has failed androgen deprivation therapy (ADT).In another embodiment, the cancer is resistant to treatment with anandrogen receptor antagonist. In another embodiment, the cancer isresistant to treatment with enzalutamide, bicalutamide, abiraterone,ARN-509, AZD-3514, galeterone, ASC-J9, flutamide, hydroxyflutamide,nilutamide, cyproterone acetate, ketoconazole, spironolactone, or anycombination thereof. In another embodiment, administering the compoundto a subject reduces the levels of AR, AR-full length (AR-FL), AR-FLwith antiandrogen resistance-conferring AR-LBD mutations, AR-splicevariant (AR-SV), gene-amplified AR, or any combination thereof, in saidsubject.

In one embodiment, the invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of AR-positive cancer that is resistant totreatment with an androgen receptor antagonist and/or a lyase inhibitor,comprising administering to said subject a therapeutically effectiveamount of compound 17

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In one embodiment, the methods of this invention are directed totreating, suppressing, reducing the incidence, reducing the severity,inhibiting, providing palliative care, or increasing the survival of asubject suffering from prostate cancer. In one embodiment, the methodsof this invention are directed to methods of treating, suppressing,reducing the incidence, reducing the severity, inhibiting, providingpalliative care, or increasing the survival of advanced prostate cancerin a subject. In one embodiment, the methods of this invention aredirected to treating, suppressing, reducing the incidence, reducing theseverity, inhibiting, providing palliative care, or increasing thesurvival of a subject suffering from castration resistant prostatecancer (CRPC). In one embodiment, the methods of this invention aredirected to treating, suppressing, reducing the incidence, reducing theseverity, inhibiting, providing palliative care, or increasing thesurvival of a subject suffering from metastatic castration resistantprostate cancer (mCRPC). In one embodiment, the methods of thisinvention are directed to treating, suppressing, reducing the incidence,reducing the severity, inhibiting, providing palliative care, orincreasing the survival of a subject suffering from non-metastaticcastration resistant prostate cancer (nmCRPC). In one embodiment, thenmCRPC is high-risk nmCRPC. In another embodiment, the subject has highor increasing prostate specific antigen (PS A) levels.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of prostate cancer (PCa) and its symptoms, orincreasing the survival of a male subject suffering from prostate cancercomprising administering to said subject a therapeutically effectiveamount of a SARD compound or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof, said compound is represented by a compound of formulas I-VII,IA-IB, and IIA-IIB or any one of compounds 13-21, 49, 50 and 17a.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of advanced prostate cancer and its symptoms,or increasing the survival of a male subject suffering from advancedprostate cancer comprising administering to said subject atherapeutically effective amount of a SARD compound or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof, said compound is represented by acompound of formulas I-VII, IA-IB, and IIA-IIB or any one of compounds13-21, 49, 50 and 17a.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of metastatic prostate cancer and itssymptoms, or increasing the survival of a male subject suffering frommetastatic prostate cancer comprising administering to said subject atherapeutically effective amount of a SARD compound or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof, said compound is represented by acompound of formulas I-VII, IA-IB, and IIA-IIB or any one of compounds13-21, 49, 50 and 17a.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of castration resistant prostate cancer(CRPC) and its symptoms, or increasing the survival of a male subjectsuffering from castration resistant prostate cancer (CRPC) comprisingadministering to said subject a therapeutically effective amount of aSARD compound or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof,said compound is represented by a compound of formulas I-VII, IA-IB, andIIA-IIB or any one of compounds 13-21, 49, 50 and 17a.

In one embodiment, the SARD compounds as described herein and/orcompositions comprising the same may be used for treating, suppressing,reducing the incidence, reducing the severity, or inhibiting theprogression of castration resistant prostate cancer (CRPC) and itssymptoms, or increasing the survival of men with castration resistantprostate cancer. In another embodiment, the CRPC is metastatic CRPC(mCRPC). In another embodiment, the CRPC is non-metastatic CRPC(nmCRPC). In one embodiment, the nmCRPC is high-risk nmCRPC. In anotherembodiment, the subject further receives androgen deprivation therapy.

As used herein, the terms “increase” and “prolong” may be usedinterchangeably having all the same meanings and qualities, whereinthese terms may in one embodiment refer to a lengthening of time. Inanother embodiment, as used herein, the terms “increase”, increasing”“increased” may be used interchangeably and refer to an entity becomingprogressively greater (as in size, amount, number, or intensity),wherein for example the entity is sex hormone-binding globulin (SHBG) orprostate-specific antigen (PSA).

In one embodiment, the compounds as described herein and/or compositionscomprising the same may be used for increasing metastasis-free survival(MFS) in a subject suffering from non-metastatic prostate cancer. In oneembodiment, the non-metastatic prostate cancer is non-metastaticadvanced prostate cancer. In another embodiment, the non-metastaticprostate cancer is non-metastatic CRPC (nmCRPC). In one embodiment, thenmCRPC is high-risk nmCRPC.

In one embodiment, the SARD compounds as described herein and/orcompositions comprising the same may be used to provide a dual action,for example treating prostate cancer and preventing metastases. In oneembodiment, the prostate cancer being treated is advanced prostatecancer. In one embodiment, the prostate cancer being treated iscastration resistant prostate cancer (CRPC). In one embodiment, theprostate cancer being treated is metastatic CRPC (mCRPC). In oneembodiment, the prostate cancer being treated is non-metastatic CRPC(nmCRPC). In one embodiment, the nmCRPC is high-risk nmCRPC.

Men with advanced prostate cancer who are at high risk for progressionto castration resistant prostate cancer (CRPC), in one embodiment, aremen on ADT with serum total testosterone concentrations greater than 20ng/dL or in another embodiment, men with advanced prostate cancer who atthe time of starting ADT had either (1) confirmed Gleason pattern 4 or 5prostate cancer, (2) metastatic prostate cancer, (3) a PSA doubling time<3 months, (4) a PSA >20 ng/mL, or (5) a PSA relapse in <3 years afterdefinitive local therapy (radical prostatectomy or radiation therapy).

Men with high risk non-metastatic castration resistant prostate cancer(high-risk nmCRPC) may include those with rapid PSA doubling times,having an expected progression-free survival of approximately 18 monthsor less (Miller K, Moul J W, Gleave M, et al. 2013. Phase III,randomized, placebo-controlled study of once-daily oral zibotentan(ZD4054) in patients with non-metastatic castration-resistant prostatecancer. Prostate Canc Prost Dis. February; 16:187-192). This relativelyrapid progression of their disease underscores the importance of noveltherapies for these individuals. In one embodiment, the PSA levels aregreater than 8 ng/mL in a subject suffering from high-risk nmCRPC. Inone embodiment, the PSA doubling time is less than 8 months in a subjectsuffering from high-risk nmCRPC. In another embodiment, the PSA doublingtime is less than 10 months in a subject suffering from high-risknmCRPC. In one embodiment, the total serum testosterone levels aregreater than 20 ng/mL in a subject suffering from high-risk nmCRPC. Inone embodiment, the serum free testosterone levels are greater thanthose observed in an orchiechtomized male in a subject suffering fromhigh-risk nmCRPC.

In one embodiment, the compounds as described herein and/or compositionscomprising the same may be used in combination with LHRH agonist orantagonist for increasing the progression free survival or overallsurvival of a subject suffering from prostate cancer. In anotherembodiment, the prostate cancer is advanced prostate cancer. In anotherembodiment, the prostate cancer is castration resistant prostate cancer(CRPC). In another embodiment, the CRPC is metastatic CRPC (mCRPC). Inanother embodiment, the CRPC is non-metastatic CRPC (nmCRPC). In oneembodiment, the nmCRPC is high-risk nmCRPC. In another embodiment, thesubject is surgically castrated. In another embodiment, the subject ischemically castrated.

In one embodiment, the compounds as described herein and/or compositionscomprising the same may be used in combination with anti-programmeddeath receptor 1 (anti-PD-1) drugs (e.g., AMP-224, nivolumab,pembrolizumab, pidilizumab, AMP-554, and the like) for increasing theprogression free survival or overall survival of a subject sufferingfrom prostate cancer. In another embodiment, the prostate cancer isadvanced prostate cancer. In another embodiment, the prostate cancer iscastration resistant prostate cancer (CRPC). In another embodiment, theCRPC is metastatic CRPC (mCRPC). In another embodiment, the CRPC isnon-metastatic CRPC (nmCRPC). In one embodiment, the nmCRPC is high-risknmCRPC. In another embodiment, the subject is surgically castrated. Inanother embodiment, the subject is chemically castrated.

In one embodiment, the compounds as described herein and/or compositionscomprising the same may be used in combination with anti-PD-L1 drugs(e.g., BMS-936559, MEDI4736, MPDL3280A, MEDI4736, MSB0010718C, and thelike) for increasing the progression free survival or overall survivalof a subject suffering from prostate cancer. In another embodiment, theprostate cancer is advanced prostate cancer. In another embodiment, theprostate cancer is castration resistant prostate cancer (CRPC). Inanother embodiment, the CRPC is metastatic CRPC (mCRPC). In anotherembodiment, the CRPC is non-metastatic CRPC (nmCRPC). In one embodiment,the nmCRPC is high-risk nmCRPC. In another embodiment, the subject issurgically castrated. In another embodiment, the subject is chemicallycastrated.

In certain embodiments, treatment of prostate cancer, advanced prostatecancer, CRPC, mCRPC and/or nmCRPC may result in clinically meaningfulimprovement in prostate cancer related symptoms, function and/orsurvival. Clinically meaningful improvements include but are not limitedto increasing radiographic progression free survival (rPFS) if cancer ismetastatic, and increasing metastasis-free survival (MFS) if cancer isnon-metastatic.

In one embodiment, the compounds as described herein and/or compositionscomprising the same may be used for increasing the survival of men withcastration resistant prostate cancer (CRPC). In another embodiment, theCRPC is metastatic CRPC (mCRPC). In another embodiment, the CRPC isnon-metastatic CRPC (nmCRPC). In one embodiment, the nmCRPC is high-risknmCRPC. In another embodiment, the subject further receives androgendeprivation therapy.

In one embodiment, levels of prostate specific antigen (PSA) considerednormal are age dependent. In one embodiment, levels of prostate specificantigen (PSA) considered normal are dependent on the size of a malesubject's prostate. In one embodiment, PSA levels in the range between2.5-10 ng/mL are considered “borderline high”. In another embodiment,PSA levels above 10 ng/mL are considered “high”.

In one embodiment, the rate of change or “PSA velocity” is high. In oneembodiment, a rate of change or “PSA velocity” greater than 0.75/year isconsidered high.

In one embodiment, this invention provides a method of lowering serumprostate specific antigen (PSA) levels in a male subject suffering fromprostate cancer, advanced prostate cancer, metastatic prostate cancer orcastration resistant prostate cancer (CRPC), comprising administering atherapeutically effective amount of a SARD compound or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof, said compound is represented by thestructure of formulas I-VII, IA-IB, and IIA-IIB or any one of compounds13-21, 49, 50 and 17a.

In one embodiment, this invention is directed to treatment of a subjectwith high or increasing PSA levels comprising administering a SARDcompound of this invention. In one embodiment, this invention isdirected to treatment of a subject with high or increasing PSA levelsdespite ongoing ADT or a history of ADT, surgical castration or despitetreatment with antiandrogens and/or LHRH agonist. In another embodiment,the treatment makes use of compounds of formulas I-VII, IA-IB, andIIA-IIB or any one of compounds 13-21, 49, 50 and 17a.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of castration resistant prostate cancer(CRPC) and its symptoms, or increasing the survival of men withcastration resistant prostate cancer comprising administering atherapeutically effective amount of a compound of formulas I-VII, IA-IB,and IIA-IIB or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the compound is compound 13. In anotherembodiment, the compound is compound 14. In another embodiment, thecompound is compound 15. In another embodiment, the compound is compound16. In another embodiment, the compound is compound 17. In anotherembodiment, the compound is compound 17a. In another embodiment, thecompound is compound 18. In another embodiment, the compound is compound19. In another embodiment, the compound is compound 20. In anotherembodiment, the compound is compound 21. In another embodiment, thecompound is compound 49. In another embodiment, the compound is compound50.

In one embodiment, this invention provides a method of secondaryhormonal therapy that reduces serum PSA in a male subject suffering fromcastration resistant prostate cancer (CRPC) comprising administering atherapeutically effective amount of a compound of formulas I-VII, IA-IB,and IIA-IIB or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the castration is surgical castration. In anotherembodiment, with regards to the methods described above, the prostatecancer depends on AR-FL and/or AR-SV for proliferation. In anotherembodiment, the cancer is resistant to treatment with an androgenreceptor antagonist. In another embodiment, the cancer is resistant totreatment with enzalutamide, bicalutamide, abiraterone, ARN-509,AZD-3514, galeterone, ASC-J9, flutamide, hydroxyflutamide, nilutamide,cyproterone acetate, ketoconazole, spironolactone, or any combinationthereof. In another embodiment, administration of the compounds offormulas I-VII, IA-IB, and IIA-IIB reduces the levels of AR, AR-fulllength (AR-FL), AR-FL with antiandrogen resistance-conferring AR-LBDmutations, AR-splice variant (AR-SV), amplifications of the AR genewithin the tumor, or any combination thereof, in the subject. In anotherembodiment, the castration is surgical castration. In anotherembodiment, the castration is chemical castration. In anotherembodiment, the CRPC is metastatic CRPC (mCRPC). In another embodiment,the CRPC is non-metastatic CRPC (nmCRPC). In one embodiment, the nmCRPCis high-risk nmCRPC. In another embodiment, the method further increasesradiographic progression free survival (rPFS) in a subject sufferingfrom a metastatic cancer. In another embodiment, the method furtherincreases metastasis-free survival (MFS) in a subject suffering fromnon-metastatic cancer. In one embodiment, the method may be used toprovide a dual action, for example treating prostate cancer andpreventing metastases. In another embodiment, the subject has failedandrogen deprivation therapy (ADT). In another embodiment, the subjectfurther receives androgen deprivation therapy (ADT). In anotherembodiment, the subject further receives LHRH agonist or antagonist. Inanother embodiment, the LHRH agonist is leuprolide acetate. In anotherembodiment, the subject had undergone orchidectomy. In anotherembodiment, the subject has high or increasing prostate specific antigen(PSA) levels. In another embodiment, the subject is a prostate cancerpatient. In another embodiment, the subject is a prostate cancer patienton ADT. In another embodiment, the subject is a prostate cancer patienton ADT with castrate levels of total T. In another embodiment, thesubject is an advanced prostate cancer patient. In another embodiment,the subject is an advanced prostate cancer patient on ADT. In anotherembodiment, the subject is an advanced prostate cancer patient on ADTwith castrate levels of total T. In another embodiment, the subject is aCRPC patient. In another embodiment, the subject is a CRPC patient onADT. In another embodiment, the subject is a CRPC patient on ADT withcastrate levels of total T. In another embodiment, the subject is ametastatic castration resistant prostate cancer (mCRPC) patient. Inanother embodiment, the subject is a mCRPC patient maintained on ADT. Inanother embodiment, the subject is a mCRPC patient maintained on ADTwith castrate levels of total T. In another embodiment, the subject is anon-metastatic castration resistant prostate cancer (nmCRPC) patient. Inanother embodiment, the subject is an nmCRPC patient maintained on ADT.In another embodiment, the subject is an nmCRPC patient maintained onADT with castrate levels of total T. In one embodiment, the nmCRPC ishigh-risk nmCRPC. In another embodiment, the method further treats,suppresses, reduces the incidence, reduces the severity, or inhibitsadvanced prostate cancer. In another embodiment, the method furtherprovides palliative treatment of advanced prostate cancer.

In one embodiment, this invention is directed to a method of reducingthe levels of AR, AR-full length, AR-FL with antiandrogenresistance-conferring AR-LBD mutations, and/or AR-splice variants in asubject, comprising administering to said subject a therapeuticallyeffective amount of a SARD compound according to this invention, or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof. In another embodiment,the reduction is achieved by degradation of said AR, AR-full length(AR-FL) and/or AR-splice variants (AR-SV). In another embodiment, thereduction is achieved by inhibition of said AR, AR-full length (AR-FL)and/or AR-splice variants (AR-SV). In another embodiment, the reductionis achieved by dual AR-SV/AR-FL degradation and AR-SV/AR-FL inhibitoryfunctions.

In one embodiment, this invention is directed to a method of reducingthe levels of AR-splice variants in a subject, comprising administeringto said subject a therapeutically effective amount of a SARD compoundaccording to this invention, or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, hydrate or any combinationthereof. In another embodiment, the method further reduces the levels ofAR-full length (AR-FL) in the subject. In another embodiment, thereduction is achieved by degradation of said AR-splice variants (AR-SV).In another embodiment, the reduction is further achieved by degradationof said AR-FL. In another embodiment, the reduction is achieved byinhibition of said AR-splice variants (AR-SV). In another embodiment,the reduction is further achieved by inhibition of said AR-FL. Inanother embodiment, the reduction is achieved by dual AR-SV degradationand AR-SV inhibitory functions. In another embodiment, the reduction isachieved by dual AR-FL degradation and AR-FL inhibitory functions.

In one embodiment, “a subject suffering from castration resistantprostate cancer” refers to a subject which has been previously treatedwith androgen deprivation therapy (ADT), has responded to the ADT andcurrently has a serum PSA >2 ng/mL or >2 ng/mL and representing a 25%increase above the nadir achieved on the ADT. In another embodiment, theterm refers to a subject which despite being maintained on androgendeprivation therapy is diagnosed to have serum PSA progression. Inanother embodiment, the subject has a castrate level of serum totaltestosterone (<50 ng/dL). In another embodiment, the subject has acastrate level of serum total testosterone (<20 ng/dL). In anotherembodiment, the subject has rising serum PSA on two successiveassessments at least 2 weeks apart. In another embodiment, the subjecthad been effectively treated with ADT. In another embodiment, thesubject has a history of serum PSA response after initiation of ADT. Inanother embodiment, the subject has been treated with ADT and had aninitial serum PSA response, but now has a serum PSA >2 ng/mL and a 25%increase above the nadir observed on ADT. In one embodiment, the CRPC ismetastatic CRPC (mCRPC). In another embodiment, the CRPC isnon-metastatic CRPC (nmCRPC). In one embodiment, the nmCRPC is high-risknmCRPC.

The term “serum PSA response” refers to, in one embodiment, at least 90%reduction in serum PSA value prior to the initiation of ADT, to <10ng/mL OR undetectable level of serum PSA (<0.2 ng/mL) at any time, or inanother embodiment to at least 50% decline from baseline in serum PSA,or in another embodiment to at least 90% decline from baseline in serumPSA, or in another embodiment to at least 30% decline from baseline inserum PSA, or in another embodiment to at least 10% decline frombaseline in serum PSA.

The term “serum PSA progression” refers to in one embodiment, a 25% orgreater increase in serum PSA and an absolute increase of 2 ng/ml ormore from the nadir; or in another embodiment, to serum PSA >2 ng/mL,or >2 ng/mL and a 25% increase above the nadir after the initiation ofandrogen deprivation therapy (ADT).

In another embodiment, the term “nadir” refers to the lowest PSA levelwhile a patient is undergoing ADT.

Testosterone can be measured as “free” (that is, bioavailable andunbound) or as “total” (including the percentage which is protein boundand unavailable) serum levels. In one embodiment, total serumtestosterone comprises free testosterone and bound testosterone.

The methods of this invention comprise administering a combination offorms of ADT and a compound of this invention. In one embodiment, formsof ADT include a LHRH agonist. In another embodiment, the LHRH agonistincludes leuprolide acetate (Lupron®) (U.S. Pat. No. 5,480,656; U.S.Pat. Nos. 5,575,987; 5,631,020; 5,643,607; 5,716,640; 5,814,342;6,036,976 which are all incorporated by reference herein) or goserelinacetate (Zoladex®) (U.S. Pat. Nos. 7,118,552; 7,220,247; 7,500,964 whichare all incorporated by reference herein). In one embodiment, forms ofADT include an LHRH antagonist. In another embodiment, the LHRHantagonist includes degarelix. In one embodiment, forms of ADT includereversible antiandrogens. In another embodiment, the antiandrogensinclude bicalutamide, flutamide, finasteride, dutasteride, enzalutamide,nilutamide, chlormadinone, abiraterone or any combination thereof. Inone embodiment, forms of ADT include bilateral orchidectomy.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of castration resistant prostate cancer(CRPC) and its symptoms, or increasing the survival of men withcastration resistant prostate cancer comprising administering atherapeutically effective amount of a combination of one or more formsof ADT and a compound of formulas I-VII, IA-IB, and IIA-IIB or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof. In another embodiment,the subject has failed androgen deprivation therapy (ADT).

In one embodiment, this invention provides a method of lowering serumPSA levels in a male subject suffering from castration resistantprostate cancer (CRPC) comprising administering a therapeuticallyeffective amount of a combination of one or more forms of ADT and acompound of formulas I-VII, IA-IB, and IIA-IIB or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the subjecthas failed androgen deprivation therapy (ADT).

In one embodiment, the methods of this invention comprise administeringa therapeutically effective amount of an antiandrogen and a compound ofthis invention. In one embodiment, the methods of this inventioncomprise administering a therapeutically effective amount of an LHRHagonist and a compound of this invention. In one embodiment, the methodsof this invention comprise administering a therapeutically effectiveamount of an antiandrogen, LHRH agonist and a compound of thisinvention. In another embodiment, the compound is compound of formulasI-VII, IA-IB, and IIA-IIB. In another embodiment, the compound is anyone of compounds 13-21, 49, 50 and 17a.

In one embodiment, the methods of this invention comprise administeringa therapeutically effective amount of a lyase inhibitor (e.g.,abiraterone) and a compound of this invention. In another embodiment,the compound is a compound of formulas I-VII, IA-IB, and IIA-IIB. Inanother embodiment, the compound is any one of compounds 13-21, 49, 50and 17a.

In another embodiment, this invention provides a method for androgendeprivation therapy (ADT) in a subject, comprising administering atherapeutically effective amount of a compound of formulas I-VII, IA-IB,and IIA-IIB or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, said subject has prostate cancer. In anotherembodiment, the prostate cancer is castration resistant prostate cancer(CRPC). In another embodiment, the CRPC is metastatic CRPC (mCRPC). Inone embodiment, the CRPC is non-metastatic castration resistant prostatecancer (nmCRPC). In one embodiment, the nmCRPC is high-risk nmCRPC. Inanother embodiment, the compound is any one of compounds 13-21, 49, 50and 17a. In another embodiment, the subject has failed androgendeprivation therapy (ADT). In another embodiment, the subject furtherreceives androgen deprivation therapy (ADT).

In one embodiment, this invention provides a method of treating prostatecancer or delaying the progression of prostate cancer comprisingadministering a SARD compound of this invention. In one embodiment, thisinvention provides a method of preventing and/or treating the recurrenceof prostate cancer comprising administering a SARD compound of thisinvention. In another embodiment, the prostate cancer is castrationresistant prostate cancer (CRPC). In another embodiment, the CRPC ismetastatic CRPC (mCRPC). In one embodiment, the CRPC is non-metastaticcastration resistant prostate cancer (nmCRPC). In one embodiment, thenmCRPC is high-risk nmCRPC.

In one embodiment, this invention provides a method of increasing thesurvival of a subject having prostate cancer, advanced prostate cancer,castration resistant prostate cancer or metastatic castration resistantprostate cancer or non-metastatic castration resistant prostate canceror high-risk non-metastatic castration resistant prostate cancer,comprising administering a compound of this invention. In anotherembodiment, administering a compound of this invention in combinationwith LHRH analogs, reversible antiandrogens (such as bicalutamide,flutamide, or enzalutamide), anti-estrogens, anticancer drugs, 5-alphareductase inhibitors, aromatase inhibitors, progestins, selectiveandrogen receptor modulators (SARMs) or agents acting through othernuclear hormone receptors. In another embodiment, the subject has failedandrogen deprivation therapy (ADT). In another embodiment the compoundis any one of compounds 13-21, 49, 50 and 17a.

The term “advanced prostate cancer” refers to metastatic cancer havingoriginated in the prostate, and having widely metastasized to beyond theprostate such as the surrounding tissues to include the seminal vesiclesthe pelvic lymph nodes or bone, or to other parts of the body. Prostatecancer pathologies are graded with a Gleason grading from 1 to 5 inorder of increasing malignancy. In another embodiment, patients withsignificant risk of progressive disease and/or death from prostatecancer should be included in the definition and that any patient withcancer outside the prostate capsule with disease stages as low as IIBclearly has “advanced” disease. In another embodiment, “advancedprostate cancer” can refer to locally advanced prostate cancer.

Men with advanced prostate cancer often receive treatment to block theproduction of androgens, which are male sex hormones that may helpprostate tumors grow. However, prostate cancers that initially respondto antiandrogen therapy eventually develop the ability to grow withoutandrogens. Such cancers are often referred to as hormone refractory,androgen independent, or castration resistant.

In one embodiment, the advanced prostate cancer is castration resistantprostate cancer.

The term “castration resistant prostate cancer” (CRPC) refers toadvanced prostate cancer that is worsening or progressing while thepatient remains on ADT or other therapies to reduce testosterone, orprostate cancer which is considered hormone refractory, hormone naïve,androgen independent or chemical or surgical castration resistant. Inanother embodiment, CRPC is a result of AR activation by intracrineandrogen synthesis. In another embodiment, CRPC is a result ofexpression of AR splice variants (AR-SV) that lack ligand binding domain(LBD). In another embodiment, CRPC is a result of expression of AR-LBDmutations with potential to resist antagonists. In another embodiment,castration resistant prostate cancer (CRPC) is an advanced prostatecancer which developed despite ongoing ADT and/or surgical castration.In one embodiment, castration resistant prostate cancer is defined asprostate cancer that continues to progress or worsen or adversely affectthe health of the patient despite prior surgical castration, continuedtreatment with gonadotropin releasing hormone agonists (e.g.,leuprolide) or antagonists (e.g., degarelix), antiandrogens (e.g.,bicalutamide, flutamide, enzalutamide, ketoconazole, aminoglutethamide),chemotherapeutic agents (e.g., docetaxel, paclitaxel, cabazitaxel,adriamycin, mitoxantrone, estramustine, cyclophosphamide), kinaseinhibitors (imatinib (Gleevec®) or gefitinib (Iressa®), cabozantinib(Cometrig™, also known as XL184)) or other prostate cancer therapies(e.g., vaccines (sipuleucel-T (Provenge®), GVAX, etc.), herbal (PC-SPES)and lyase inhibitor (abiraterone)) as evidenced by increasing or higherserum levels of prostate specific antigen (PSA), metastasis, bonemetastasis, pain, lymph node involvement, increasing size or serummarkers for tumor growth, worsening diagnostic markers of prognosis, orpatient condition.

In one embodiment, castration resistant prostate cancer is defined ashormone naïve prostate cancer.

Many early prostate cancers require androgens for growth, but advancedprostate cancers are in some embodiments, androgen-independent, orhormone naïve. In one embodiment, in men with castration resistantprostate cancer, the tumor cells may have the ability to grow in theabsence of androgens (hormones that promote the development andmaintenance of male sex characteristics).

In one embodiment, the term “androgen deprivation therapy” (ADT) or“traditional androgen deprivation therapy” is directed to orchiectomy(surgical castration) wherein the surgeon removes the testicles. Inanother embodiment, the term “androgen deprivation therapy” or“traditional androgen deprivation therapy” is directed to administeringluteinizing hormone-releasing hormone (LHRH) analogs: these drugs lowerthe amount of testosterone made by the testicles. Examples of LHRHanalogs available in the United States include leuprolide (Lupron®,Viadur®, Eligard®), goserelin (Zoladex®), triptorelin (Trelstar®), andhistrelin (Vantas®). In another embodiment, the term “androgendeprivation therapy” or “traditional androgen deprivation therapy” isdirected to administering antiandrogens: Antiandrogens block the body'sability to use any androgens. Even after orchiectomy or during treatmentwith LHRH analogs, a small amount of androgens is still made by theadrenal glands. Examples of antiandrogens drugs include enzalutamide(Xtandi®), flutamide (Eulexin®), bicalutamide (Casodex®), and nilutamide(Nilandron®). In another embodiment, the term “androgen deprivationtherapy” or “traditional androgen deprivation therapy” is directed toadministering luteinizing hormone-releasing hormone (LHRH) antagonistssuch as abarelix (Plenaxis®) or degarelix (Firmagon®) (approved for useby the FDA in 2008 to treat advanced prostate cancer). In anotherembodiment, the term “androgen deprivation therapy” or “traditionalandrogen deprivation therapy” is directed to administering 5α-reductaseinhibitors such as finasteride (Proscar®) and dutasteride (Avodart®):5α-reductase inhibitors block the body's ability to convert testosteroneto the more active androgen, 5α-dihydrotestosterone (DHT). In anotherembodiment, the term “androgen deprivation therapy” or “traditionalandrogen deprivation therapy” is directed to administering inhibitors oftestosterone biosynthesis such as ketoconazole (Nizoral®). In anotherembodiment, the term “androgen deprivation therapy” or “traditionalandrogen deprivation therapy” is directed to administering estrogenssuch as diethylstilbestrol or 17β-estradiol. In another embodiment, theterm “androgen deprivation therapy” or “traditional androgen deprivationtherapy” is directed to administering 17α-hydroxylase/C17,20 lyase(CYP17A1) inhibitors such as abiraterone (Zytiga®).

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, increasingthe survival, or inhibiting an antiandrogen-resistant prostate cancer.In another embodiment, the antiandrogen is bicalutamide,hydroxyflutamide, flutamide, or enzalutamide.

In one embodiment, this invention provides a method of treating,suppressing, reducing the incidence, reducing the severity, increasingthe survival, or inhibiting an abiraterone-resistant prostate cancer.

Muscle atrophy (MA) is characterized by wasting away or diminution ofmuscle and a decrease in muscle mass. For example, post-polio MA is amuscle wasting that occurs as part of the post-polio syndrome (PPS). Theatrophy includes weakness, muscle fatigue, and pain.

Another type of MA is X-linked spinal-bulbar muscular atrophy (SBMA—alsoknown as Kennedy's Disease). This disease arises from a defect in theandrogen receptor gene on the X chromosome, affects only males, and itsonset is in late adolescence to adulthood. Proximal limb and bulbarmuscle weakness results in physical limitations including dependence ona wheelchair in some cases. The mutation results in an extendedpolyglutamine tract at the N-terminal domain of the androgen receptor(polyQ AR). Binding and activation of the polyQ AR by endogeneousandrogens (testosterone and DHT) results in unfolding and nucleartranslocation of the mutant androgen receptor. These steps are requiredfor pathogenesis and results in partial loss of transactivation function(i.e., an androgen insensitivity) and a poorly understood neuromusculardegeneration. Currently there are no disease-modifying treatments butrather only symptom directed treatments. Efforts to target the polyQ ARas the proximal mediator of toxicity by harnessing cellular machinery topromote its degradation hold promise for therapeutic intervention.Selective androgen receptor degraders such as those reported herein bindto and degrade a variety of androgen receptors (full length, splicevariant, antiandrogen resistance mutants, etc.), indicating that theyare promising leads for treatment of SBMA. This view is supported by theobservation that peripheral polyQ AR anti-sense therapy rescues diseasein mouse models of SBMA (Cell Reports 7, 774-784, May 8, 2014).

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of the Kennedy's disease comprisingadministering therapeutically effective amount of a compound of formulasI-VII, IA, IIA or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the compound is any one of compounds 13-21, 49,50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of Kennedy's disease in a subject, comprisingadministering to said subject a therapeutically effective amount ofcompound 17

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

As used herein, “androgen receptor associated conditions” or “androgensensitive diseases or disorders” are conditions, diseases, or disordersthat are modulated by or whose pathogenesis is dependent upon theactivity of the androgen receptor. The androgen receptor is expressed inmost tissues of the body however it is overexpressed in, inter alia, theprostate and skin. ADT has been the mainstay of prostate cancertreatment for many years, and SARD may also be useful also in treatingvarious prostate cancers, benign prostatic hypertrophy, prostamegaly,and other maladies of the prostate.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of benign prostatic hypertrophy comprisingadministering a therapeutically effective amount of a compound offormulas I-VII, IA, IIA or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the compound is any one of compounds 13-21, 49,50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of prostamegaly comprising administering atherapeutically effective amount of a compound of formulas I-VII, IA,IIA or its isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, hydrate or any combination thereof. In anotherembodiment, the compound is any one of compounds 13-21, 49, 50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of hyperproliferative prostatic disorders anddiseases comprising administering a therapeutically effective amount ofa compound of formulas I-VII, IA-IB, and IIA-IIB or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 13-21, 49, 50 and 17a.

The effect of the AR on the skin is apparent in the gender dimorphismand puberty related dermatological problems common to teens and earlyadults. The hyperandrogenism of puberty stimulates terminal hair growth,sebum production, and predisposes male teens to acne, acne vulgaris,seborrhea, excess sebum, hidradenitis suppurativa, hirsutism,hypertrichosis, hyperpilosity, androgenic alopecia, male patternbaldness, and other dermatological maladies. Although antiandrogenstheoretically should prevent the hyperandrogenic dermatological diseasesdiscussed, they are limited by toxicities, sexual side effects, and lackof efficacy when topically applied. The SARDs of this invention potentlyinhibit ligand-dependent and ligand-independent AR activation, and haveshort biological half-lives in the serum, suggesting that topicallyformulated SARDs of this invention could be applied to the areasaffected by acne, seborrheic dermatitis, and/or hirsutism without riskof systemic side effects.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of acne comprising administering atherapeutically effective amount of a compound of formulas I-VII, IA-IB,and IIA-IIB or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the compound is any one of compounds 13-21, 49,50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of acne vulgaris comprising administering atherapeutically effective amount of a compound of formulas I-VII, IA-IB,and IIA-IIB or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the compound is any one of compounds 13-21, 49,50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of seborrhea comprising administering atherapeutically effective amount of a compound of formulas I-VII, IA-IB,and IIA-IIB or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the compound is any one of compounds 13-21, 49,50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of seborrheic dermatitis comprisingadministering a therapeutically effective amount of a compound offormulas I-VII, IA-IB, and IIA-IIB or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, hydrate or anycombination thereof. In another embodiment, the compound is any one ofcompounds 13-21, 49, 50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of hidradenitis supporativa comprisingadministering a therapeutically effective amount of a compound offormulas I-VII, IA-IB, and IIA-IIB or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, hydrate or anycombination thereof. In another embodiment, the compound is any one ofcompounds 13-21, 49, 50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of hirsutism comprising administering atherapeutically effective amount of a compound of formulas I-VII, IA-IB,and IIA-IIB or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the compound is any one of compounds 13-21, 49,50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of hypertrichosis comprising administering atherapeutically effective amount of a compound of formulas I-VII, IA,IIA or its isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, hydrate or any combination thereof. In anotherembodiment, the compound is any one of compounds 13-21, 49, 50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of hyperpilosity comprising administering atherapeutically effective amount of a compound of formulas I-VII, IA-IB,and IIA-IIB or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the compound is any one of compounds 13-21, 49,50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of alopecia comprising administering atherapeutically effective amount of a compound of formulas I-VII, IA-IB,and IIA-IIB or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the compound is any one of compounds 13-21, 49,50 and 17a.

In some embodiments, the compounds as described herein and/orcompositions may be used for applications in or treating hair loss,alopecia, androgenic alopecia, alopecia areata, alopecia secondary tochemotherapy, alopecia secondary to radiation therapy, alopecia inducedby scarring or alopecia induced by stress. In one embodiment, “hairloss”, or “alopecia”, refers to baldness as in the very common type ofmale-pattern baldness. Baldness typically begins with patch hair loss onthe scalp and sometimes progresses to complete baldness and even loss ofbody hair. Hair loss affects both males and females.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of androgenic alopecia comprisingadministering a therapeutically effective amount of a compound offormula I-VII, IA-IB, and IIA-IIB or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, hydrate or anycombination thereof. In another embodiment, the compound is any one ofcompounds 13-21, 49, 50 and 17a.

SARDs of this invention may also be useful in the treatment of hormonalconditions in females such as precocious puberty, early puberty,dysmenorrhea, amenorrhea, multilocular uterus syndrome, endometriosis,hysteromyoma, abnormal uterine bleeding, early menarche, fibrocysticbreast disease, fibroids of the uterus, ovarian cysts, polycystic ovarysyndrome, pre-eclampsia, eclampsia of pregnancy, preterm labor,premenstrual syndrome, and vaginal dryness.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of precocious puberty or early pubertycomprising administering a therapeutically effective amount of acompound of formulas I-VII, IA-IB, and IIA-IIB or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 13-21, 49, 50 and 17a.

In one embodiment, the invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of a hyperandrogenic hormonal condition in afemale, comprising administering to said subject a therapeuticallyeffective amount of compound 17

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In one embodiment, the hyperandrogenic hormonal condition in a female isprecocious puberty, early puberty, dysmenorrhea, amenorrhea,multilocular uterus syndrome, endometriosis, hysteromyoma, abnormaluterine bleeding, early menarche, fibrocystic breast disease, fibroidsof the uterus, ovarian cysts, polycystic ovary syndrome, pre-eclampsia,eclampsia of pregnancy, preterm labor, premenstrual syndrome, and/orvaginal dryness.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of dysmenorrhea or amenorrhea comprisingadministering a therapeutically effective amount of a compound offormulas I-VII, IA-IB, and IIA-IIB or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, hydrate or anycombination thereof. In another embodiment, the compound is any one ofcompounds 13-21, 49, 50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of multilocular uterus syndrome,endometriosis, hysteromyoma, or abnormal uterine bleeding comprisingadministering a therapeutically effective amount of a compound offormulas I-VII, IA-IB, and IIA-IIB or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, hydrate or anycombination thereof. In another embodiment, the compound is any one ofcompounds 13-21, 49, 50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of any hyper-androgenic diseases (for examplepolycystic ovary syndrome (PCOS)) comprising administering atherapeutically effective amount of a compound of formulas I-VII, IA,IIA or its isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, hydrate or any combination thereof. In anotherembodiment, the compound is any one of compounds 13-21, 49, 50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of fibrocystic breast disease, fibroids ofthe uterus, ovarian cysts, or polycystic ovary syndrome comprisingadministering a therapeutically effective amount of a compound offormulas I-VII, IA-IB, and IIA-IIB or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, hydrate or anycombination thereof. In another embodiment, the compound is any one ofcompounds 13-21, 49, 50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of pre-eclampsia, eclampsia of pregnancy,preterm labor, premenstrual syndrome, or vaginal dryness comprisingadministering a therapeutically effective amount of a compound offormulas I-VII, IA-IB, and IIA-IIB or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, hydrate or anycombination thereof. In another embodiment, the compound is any one ofcompounds 13-21, 49, 50 and 17a.

SARDS of this invention may also find utility in treatment of sexualperversion, hypersexuality, paraphilias, androgen psychosis,virilization, androgen insensitivity syndromes (AIS) such as complete MS(CMS) and partial MS (PAIS), and improving ovulation in an animal.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of sexual perversion, hypersexuality, orparaphilias comprising administering a therapeutically effective amountof a compound of formulas I-VII, IA-IB, and IIA-IIB or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 13-21, 49, 50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of androgen psychosis comprisingadministering a therapeutically effective amount of a compound offormulas I-VII, IA-IB, and IIA-IIB or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, hydrate or anycombination thereof. In another embodiment, the compound is any one ofcompounds 13-21, 49, 50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of virilization comprising administering atherapeutically effective amount of a compound of formulas I-VII, IA-IB,and IIA-IIB or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the compound is any one of compounds 13-21, 49,50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of androgen insensitivity syndromescomprising administering a therapeutically effective amount of acompound of formulas I-VII, IA-IB, and IIA-IIB or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 13-21, 49, 50 and 17a. In one embodiment, theandrogen insensitivity syndrome is a complete androgen insensitivitysyndrome. In another embodiment, the androgen insensitivity syndrome isa partial androgen insensitivity syndrome.

In one embodiment, this invention is directed to a method of increasing,modulating, or improving ovulation in an animal comprising administeringa therapeutically effective amount of a compound of formulas I-VII,IA-IB, and IIA-IIB or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the compound is any one of compounds 13-21, 49,50 and 17a.

SARDs of this invention may also be useful for the treating ofhormone-dependent cancers such as prostate cancer, breast cancer,testicular cancer, ovarian cancer, hepatocellular carcinoma, urogenitalcancer, etc. Further, local or systemic SARD administration may beuseful for treatment of precursors of hormone dependent cancers such asprostatic intraepithelial neoplasia (PIN) and atypical small acinarproliferation (ASAP).

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of breast cancer comprising administering atherapeutically effective amount of a compound of formulas I-VII, IA-IB,and IIA-IIB or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the compound is any one of compounds 13-21, 49,50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of testicular cancer comprising administeringa therapeutically effective amount of a compound of formulas I-VII,IA-IB, and IIA-IIB or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the compound is any one of compounds 13-21, 49,50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of uterine cancer comprising administering atherapeutically effective amount of a compound of formulas I-VII, IA-IB,and IIA-IIB or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the compound is any one of compounds 13-21, 49,50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of ovarian cancer comprising administering atherapeutically effective amount of a compound of formulas I-VII, IA-IB,and IIA-IIB or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the compound is any one of compounds 13-21, 49,50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of urogenital cancer comprising administeringa therapeutically effective amount of a compound of formulas I-VII,IA-IB, and IIA-IIB or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the compound is any one of compounds 13-21, 49,50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of precursors of prostate cancer comprisinglocal or systemic administration of a therapeutically effective amountof a compound of formulas I-VII, IA-IB, and IIA-IIB or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 13-21, 49, 50 and 17a. In one embodiment, theprecursor of prostate cancers is pro static intraepithelial neoplasia(PIN). In another embodiment, the precursor of prostate cancer isatypical small acinar proliferation (ASAP).

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of AR related solid tumors. In anotherembodiment, the tumor is hepatocellular carcinoma (HCC). In anotherembodiment, the tumor is bladder cancer. Serum testosterone may bepositively linked to the development of HCC. Based on epidemiologic,experimental observations, and notably the fact that men have asubstantially higher risk of bladder cancer than women, androgens and/orthe AR also play a role in bladder cancer initiation.

SARD of this invention may also be useful for the treating other cancerscontaining AR such as breast, brain, skin, ovarian, bladder, lymphoma,liver, kidney, pancreas, endometrium, lung (e.g., NSCLC), colon,perianal adenoma, osteosarcoma, CNS, melanoma, hypercalcemia ofmalignancy and metastatic bone disease etc.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of hypercalcemia of malignancy comprisingadministering a therapeutically effective amount of a compound offormulas I-VII, IA-IB, and IIA-IIB or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, hydrate or anycombination thereof. In another embodiment, the compound is any one ofcompounds 13-21, 49, 50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of metastatic bone disease comprisingadministering a therapeutically effective amount of a compound offormulas I-VII, IA-IB, and IIA-IIB or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, hydrate or anycombination thereof. In another embodiment, the compound is any one ofcompounds 13-21, 49, 50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of brain cancer comprising administering atherapeutically effective amount of a compound of formulas I-VII, IA-IB,and IIA-IIB or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the compound is any one of compounds 13-21, 49,50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of skin cancer comprising administering atherapeutically effective amount of a compound of formulas I-VII, IA-IB,and IIA-IIB or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the compound is any one of compounds 13-21, 49,50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of ovarian cancer comprising administering atherapeutically effective amount of a compound of formulas I-VII, IA-IB,and IIA-IIB or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the compound is any one of compounds 13-21, 49,50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of bladder cancer comprising administering atherapeutically effective amount of a compound of formulas I-VII, IA-IB,and IIA-IIB or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the compound is any one of compounds 13-21, 49,50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of lymphoma comprising administering atherapeutically effective amount of a compound of formulas I-VII, IA-IB,and IIA-IIB or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the compound is any one of compounds 13-21, 49,50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of liver cancer comprising administering atherapeutically effective amount of a compound of formulas I-VII, IA-IB,and IIA-IIB or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the compound is any one of compounds 13-21, 49,50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of renal cancer comprising administering atherapeutically effective amount of a compound of formulas I-VII, IA-IB,and IIA-IIB or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the compound is any one of compounds 13-21, 49,50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of osteosarcoma comprising administering atherapeutically effective amount of a compound of formulas I-VII, IA-IB,and IIA-IIB or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the compound is any one of compounds 13-21, 49,50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of pancreatic cancer comprising administeringa therapeutically effective amount of a compound of formulas I-VII,IA-IB, and IIA-IIB or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the compound is any one of compounds 13-21, 49,50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of endometrial cancer comprisingadministering a therapeutically effective amount of a compound offormulas I-VII, IA-IB, and IIA-IIB or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, hydrate or anycombination thereof. In another embodiment, the compound is any one ofcompounds 13-21, 49, 50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of lung cancer comprising administering atherapeutically effective amount of a compound of formulas I-VII, IA-IB,and IIA-IIB or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the compound is any one of compounds 13-21, 49,50 and 17a. In one embodiment, the lung cancer is non-small cell lungcancer (NSCLC).

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of a central nervous system cancer comprisingadministering a therapeutically effective amount of a compound offormulas I-VII, IA-IB, and IIA-IIB or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, hydrate or anycombination thereof. In another embodiment, the compound is any one ofcompounds 13-21, 49, 50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of colon cancer comprising administering atherapeutically effective amount of a compound of formulas I-VII, IA-IB,and IIA-IIB or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the compound is any one of compounds 13-21, 49,50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of melanoma comprising administering atherapeutically effective amount of a compound of formulas I-VII, IA-IB,and IIA-IIB or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the compound is any one of compounds 13-21, 49,50 and 17a.

SARDs of this invention may also be useful for the treating ofnon-hormone-dependent cancers. Non-hormone dependent cancers includeliver, salivary duct, etc.

In one embodiment, the SARDs of this invention are used for treatinggastric cancer. In another embodiment, the SARDs of this invention areused for treating salivary duct carcinoma. In another embodiment, theSARDs of this invention are used for treating bladder cancer. In anotherembodiment, the SARDs of this invention are used for treating esophagealcancer. In another embodiment, the SARDs of this invention are used fortreating pancreatic cancer. In another embodiment, the SARDs of thisinvention are used for treating colon cancer. In another embodiment, theSARDs of this invention are used for treating non-small cell lungcancer. In another embodiment, the SARDs of this invention are used fortreating renal cell carcinoma.

AR plays a role in cancer initiation in hepatocellular carcinoma (HCC).Therefore, targeting AR may be appropriate treatment for patients withearly stage HCC. In late-stage HCC disease, there is evidence thatmetastasis is suppressed by androgens. In another embodiment, the SARDsof this invention are used for treating hepatocellular carcinoma (HCC).

Locati et al. (Head & Neck, 2016, 724-731) demonstrated the use ofandrogen deprivation therapy (ADT) in AR-expressing recurrent/metastaticsalivary gland cancers was confirmed to improve progression freesurvival and overall survival endpoints. In another embodiment, theSARDs of this invention are used for treating salivary gland cancer.

Kawahara et al. (Oncotarget, 2015, 6(30), 29860-29876) demonstrated thatELK1 inhibition, together with AR inactivation, has the potential ofbeing a therapeutic approach for bladder cancer. McBeth et al. (Int. JEndocrinology, 2015, Vol 2015 1-10) suggested that the combination ofanti-androgen therapy plus glucocorticoids since bladder cancer isbelieved to have an inflammatory etiology. In another embodiment, theSARDs of this invention are used for treating bladder cancer.

In one embodiment, the invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of AR-expressing cancer in a subject,comprising administering to said subject a therapeutically effectiveamount of compound 17

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In one embodiment, AR-expressing cancer is a cancer associated withpartial androgen insensitivity syndromes (PAIS), cancer of the fallopiantubes or peritoneum, salivary gland cancer, esophageal cancer, bladdercancer, melanoma, mantle cell lymphoma, hepatocellular carcinoma, renalcell carcinoma, non-small cell lung cancer (NSCLC), gastric cancer,and/or colon cancer. In one embodiment, the cancer associated withpartial androgen insensitivity syndromes (PAIS) is gonadal tumors and/orseminoma.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of amyotrophic lateral sclerosis (ALS) in asubject, comprising administering a therapeutically effective amount ofthe compound of formulas I-VII, IA-IB, and IIA-IIB or its isomer,pharmaceutically acceptable salt, pharmaceutical product, polymorph,hydrate or any combination thereof. In another embodiment, the compoundis any one of compounds 13-21, 49, 50 and 17a.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of amyotrophic lateral sclerosis (ALS) in asubject, comprising administering to said subject a therapeuticallyeffective amount of compound 17

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In one embodiment, the invention is directed to a method of treatingabdominal aortic aneurysm (AAA) in a subject, comprising administeringto said subject a therapeutically effective amount of compound 17

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of uterine fibroids in a subject, comprisingadministering a therapeutically effective amount of the compound offormulas I-VII, IA-IB, and IIA-IIB or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, hydrate or anycombination thereof. In another embodiment, the compound is any one ofcompounds 13-21, 49, 50 and 17a.

In one embodiment, this invention provides a method of treating asubject suffering from a wound, or reducing the incidence of, ormitigating the severity of, or enhancing or hastening healing of a woundin a subject, the method comprises administering to said subject atherapeutically effective amount of a compound of formulas I-VII, IA-IB,and IIA-IIB or its isomer, pharmaceutically acceptable salt,pharmaceutical product, polymorph, hydrate or any combination thereof.In another embodiment, the compound is any one of compounds 13-21, 49,50 and 17a.

In one embodiment, this invention provides a method of treating asubject suffering from a burn, or reducing the incidence of, ormitigating the severity of, or enhancing or hastening healing of a burnin a subject, the method comprises administering to said subject atherapeutically effective amount of a compound of formulas I-VII, IA,IIA or its isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, hydrate or any combination thereof. In anotherembodiment, the compound is any one of compounds 13-21, 49, 50 and 17a.

Wounds and/or ulcers are normally found protruding from the skin or on amucosal surface or as a result of an infarction in an organ. A wound maybe a result of a soft tissue defect or a lesion or of an underlyingcondition. In one embodiment, the term “wound” denotes a bodily injurywith disruption of the normal integrity of tissue structures. The termis also intended to encompass the terms “sore”, “lesion”, “necrosis” and“ulcer”. In one embodiment, the term “sore” refers to any lesion of theskin or mucous membranes and the term “ulcer” refers to a local defect,or excavation, of the surface of an organ or tissue, which is producedby the sloughing of necrotic tissue. Lesion generally relates to anytissue defect. Necrosis is related to dead tissue resulting frominfection, injury, inflammation or infarctions. All of these areencompassed by the term “wound”, which denotes any wound at anyparticular stage in the healing process including the stage before anyhealing has initiated or even before a specific wound like a surgicalincision is made (prophylactic treatment).

Examples of wounds which can be prevented and/or treated in accordancewith the present invention are, e.g., aseptic wounds, contused wounds,incised wounds, lacerated wounds, non-penetrating wounds (i.e. wounds inwhich there is no disruption of the skin but there is injury tounderlying structures), open wounds, penetrating wounds, perforatingwounds, puncture wounds, septic wounds, subcutaneous wounds, etc.Examples of sores are bed sores, canker sores, chrome sores, cold sores,pressure sores etc. Examples of ulcers are, e.g., peptic ulcer, duodenalulcer, gastric ulcer, gouty ulcer, diabetic ulcer, hypertensive ischemiculcer, stasis ulcer, ulcus cruris (venous ulcer), sublingual ulcer,submucous ulcer, symptomatic ulcer, trophic ulcer, tropical ulcer,veneral ulcer, e.g. caused by gonorrhoea (including urethritis,endocervicitis and proctitis). Conditions related to wounds or soreswhich may be successfully treated according to the invention are burns,anthrax, tetanus, gas gangrene, scalatina, erysipelas, sycosis barbae,folliculitis, impetigo contagiosa, or impetigo bullosa, etc. There isoften a certain overlap between the use of the terms “wound” and “ulcer”and “wound” and “sore” and, furthermore, the terms are often used atrandom. Therefore, as mentioned above, in the present context the term“wounds” encompasses the term “ulcer”, “lesion”, “sore” and“infarction”, and the terms are indiscriminately used unless otherwiseindicated.

The kinds of wounds to be treated according to the invention includealso i) general wounds such as, e.g., surgical, traumatic, infectious,ischemic, thermal, chemical and bullous wounds; ii) wounds specific forthe oral cavity such as, e.g., post-extraction wounds, endodontic woundsespecially in connection with treatment of cysts and abscesses, ulcersand lesions of bacterial, viral or autoimmunological origin, mechanical,chemical, thermal, infectious and lichenoid wounds;

herpes ulcers, stomatitis aphthosa, acute necrotising ulcerativegingivitis and burning mouth syndrome are specific examples; and iii)wounds on the skin such as, e.g., neoplasm, burns (e.g. chemical,thermal), lesions (bacterial, viral, autoimmunological), bites andsurgical incisions. Another way of classifying wounds is as i) smalltissue loss due to surgical incisions, minor abrasions and minor bites,or as ii) significant tissue loss. The latter group includes ischemiculcers, pressure sores, fistulae, lacerations, severe bites, thermalburns and donor site wounds (in soft and hard tissues) and infarctions.

In other aspects of the invention, the wound to be prevented and/ortreated is selected from the group consisting of aseptic wounds,infarctions, contused wounds, incised wounds, lacerated wounds,non-penetrating wounds, open wounds, penetrating wounds, perforatingwounds, puncture wounds, septic wounds and subcutaneous wounds.

Other wounds which are of importance in connection with the presentinvention are wounds like ischemic ulcers, pressure sores, fistulae,severe bites, thermal burns and donor site wounds.

Ischemic ulcers and pressure sores are wounds, which normally only healvery slowly and especially in such cases an improved and more rapidhealing is of course of great importance for the patient. Furthermore,the costs involved in the treatment of patients suffering from suchwounds are markedly reduced when the healing is improved and takes placemore rapidly.

Donor site wounds are wounds which e.g. occur in connection with removalof hard tissue from one part of the body to another part of the bodye.g. in connection with transplantation. The wounds resulting from suchoperations are very painful and an improved healing is therefore mostvaluable.

The term “skin” is used in a very broad sense embracing the epidermallayer of the skin and in those cases where the skin surface is more orless injured also the dermal layer of the skin. Apart from the stratumcorneum, the epidermal layer of the skin is the outer (epithelial) layerand the deeper connective tissue layer of the skin is called the dermis.

Since the skin is the most exposed part of the body, it is particularlysusceptible to various kinds of injuries such as, e.g., ruptures, cuts,abrasions, burns and frostbites or injuries arising from variousdiseases. Furthermore, much skin is often destroyed in accidents.However, due to the important barrier and physiologic function of theskin, the integrity of the skin is important to the well-being of theindividual, and any breach or rupture represents a threat that must bemet by the body in order to protect its continued existence.

Apart from injuries on the skin, injuries may also be present in allkinds of tissues (i.e. soft and hard tissues). Injuries on soft tissuesincluding mucosal membranes and/or skin are especially relevant inconnection with the present invention.

Healing of a wound on the skin or on a mucosal membrane undergoes aseries of stages that results either in repair or regeneration of theskin or mucosal membrane. In recent years, regeneration and repair havebeen distinguished as the two types of healing that may occur.Regeneration may be defined as a biological process whereby thearchitecture and function of lost tissue are completely renewed. Repair,on the other hand, is a biological process whereby continuity ofdisrupted tissue is restored by new tissues which do not replicate thestructure and function of the lost ones.

The majority of wounds heal through repair, meaning that the new tissueformed is structurally and chemically unlike the original tissue (scartissue). In the early stage of the tissue repair, one process which isalmost always involved is the formation of a transient connective tissuein the area of tissue injury. This process starts by formation of a newextracellular collagen matrix by fibroblasts. This new extracellularcollagen matrix is then the support for a connective tissue during thefinal healing process. The final healing is, in most tissues, a scarformation containing connective tissue. In tissues which haveregenerative properties, such as, e.g., skin and bone, the final healingincludes regeneration of the original tissue. This regenerated tissuehas frequently also some scar characteristics, e.g. a thickening of ahealed bone fracture.

Under normal circumstances, the body provides mechanisms for healinginjured skin or mucosa in order to restore the integrity of the skinbarrier or the mucosa. The repair process for even minor ruptures orwounds may take a period of time extending from hours and days to weeks.However, in ulceration, the healing can be very slow and the wound maypersist for an extended period of time, i.e. months or even years.

Burns are associated with reduced testosterone levels, and hypogonadismis associated with delayed wound healing. In one embodiment, the methodsof this invention, provide for treating a subject suffering from a woundor a burn via the administration of a SARD according to this invention.In one embodiment, the SARD promotes resolving of the burn or wound, orin another embodiment, participates in the healing process of a burn ora wound, or in another embodiment, treats a secondary complication of aburn or wound.

In one embodiment, the treatment of burns or wounds further incorporatesthe use of additional growth factors like epidermal growth factor (EGF),transforming growth factor-α (TGF-α), platelet derived growth factor(PDGF), fibroblast growth factors (FGFs) including acidic fibroblastgrowth factor (α-FGF) and basic fibroblast growth factor (β-FGF),transforming growth factor-β (TGF-β) and insulin like growth factors(IGF-1 and IGF-2), or any combination thereof, which are promoters ofwound healing.

Wound healing may be measured by many procedures known in the art,including wound tensile strength, hydroxyproline or collagen content,procollagen expression, and re-epithelialization. As an example, a SARDas described herein is administered orally or topically, at a dosage ofabout 0.1-1 mg per day. Therapeutic effectiveness is measured aseffectiveness in enhancing wound healing. Enhanced wound healing may bemeasured by known techniques such as decrease in healing time, increasein collagen density, increase in hydroxyproline, reduction incomplications, increase in tensile strength, and increased cellularityof scar tissue.

In one embodiment, the terms “treating” or “treatment” includespreventative as well as disorder remitative treatment. The terms“reducing”, “suppressing” and “inhibiting” have their commonlyunderstood meaning of lessening or decreasing, in another embodiment, ordelaying, in another embodiment, or reducing, in another embodiment theincidence, severity or pathogenesis of a disease, disorder or condition.In some embodiments, the term treatment refers to delayed progressionof, prolonged remission of, reduced incidence of, or amelioration ofsymptoms associated with the disease, disorder or condition. In oneembodiment, the terms “treating” “reducing”, “suppressing” or“inhibiting” refer to a reduction in morbidity, mortality, or acombination thereof, in association with the indicated disease, disorderor condition. In one embodiment, the term “progression” refers to anincreasing in scope or severity, advancing, growing or becoming worse.The term “recurrence” means, in another embodiment, the return of adisease after a remission. In one embodiment, the methods of treatmentof the invention reduce the severity of the disease, or in anotherembodiment, symptoms associated with the disease, or in anotherembodiment, reduces the number of biomarkers expressed during disease.

In one embodiment, the term “treating” and its included aspects, refersto the administration to a subject with the indicated disease, disorderor condition, or in some embodiments, to a subject predisposed to theindicated disease, disorder or condition. The term “predisposed to” isto be considered to refer to, inter alia, a genetic profile or familialrelationship which is associated with a trend or statistical increase inincidence, severity, etc. of the indicated disease. In some embodiments,the term “predisposed to” is to be considered to refer to inter alia, alifestyle which is associated with increased risk of the indicateddisease. In some embodiments, the term “predisposed to” is to beconsidered to refer to inter alia, the presence of biomarkers which areassociated with the indicated disease, for example, in cancer, the term“predisposed to” the cancer may comprise the presence of precancerousprecursors for the indicated cancer.

In some embodiments, the term “reducing the pathogenesis” is to beunderstood to encompass reducing tissue damage, or organ damageassociated with a particular disease, disorder or condition. In anotherembodiment, the term “reducing the pathogenesis” is to be understood toencompass reducing the incidence or severity of an associated disease,disorder or condition, with that in question. In another embodiment, theterm “reducing the pathogenesis” is to be understood to encompassreducing the number of associated diseases, disorders or conditions withthe indicated, or symptoms associated thereto.

Pharmaceutical Compositions

In some embodiments, this invention provides methods of use whichcomprise administering a composition comprising the described compounds.As used herein, “pharmaceutical composition” means a “therapeuticallyeffective amount” of the active ingredient, i.e. the compound of thisinvention, together with a pharmaceutically acceptable carrier ordiluent. A “therapeutically effective amount” as used herein refers tothat amount which provides a therapeutic effect for a given conditionand administration regimen.

As used herein, the term “administering” refers to bringing a subject incontact with a compound of the present invention. As used herein,administration can be accomplished in vitro, i.e. in a test tube, or invivo, i.e. in cells or tissues of living organisms, for example humans.In one embodiment, the present invention encompasses administering thecompounds of the present invention to a male subject. In one embodiment,the present invention encompasses administering the compounds of thepresent invention to a female subject.

This invention provides, in other embodiments, pharmaceutical productsof the compounds described herein. The term “pharmaceutical product”refers, in other embodiments, to a composition suitable forpharmaceutical use (pharmaceutical composition), for example, asdescribed herein.

The compounds of the invention can be administered alone or as an activeingredient of a formulation. Thus, the present invention also includespharmaceutical compositions of compounds of formulas I-VII, IA-IB, andIIA-IIB, containing, for example, one or more pharmaceuticallyacceptable carriers.

Numerous standard references are available that describe procedures forpreparing various formulations suitable for administering the compoundsaccording to the invention. Examples of potential formulations andpreparations are contained, for example, in the Handbook ofPharmaceutical Excipients, American Pharmaceutical Association (currentedition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman andSchwartz, editors) current edition, published by Marcel Dekker, Inc., aswell as Remington's Pharmaceutical Sciences (Arthur Osol, editor),1553-1593 (current edition).

The mode of administration and dosage form are closely related to thetherapeutic amounts of the compounds or compositions which are desirableand efficacious for the given treatment application.

The pharmaceutical compositions containing a compound of this inventioncan be administered to a subject by any method known to a person skilledin the art, such as orally, parenterally, intravascularly,paracancerally, transmucosally, transdermally, intramuscularly,intranasally, intravenously, intradermally, subcutaneously,sublingually, intraperitoneally, intraventricularly, intracranially,intravaginally, by inhalation, rectally, intratumorally, or by any meansin which the composition can be delivered to tissue (e.g., needle orcatheter). Alternatively, topical administration may be desired forapplication to dermal, ocular, or mucosal surfaces. Another method ofadministration is via aspiration or aerosol formulation. Further, inanother embodiment, the pharmaceutical compositions may be administeredtopically to body surfaces, and are thus formulated in a form suitablefor topical administration. Suitable topical formulations include gels,ointments, creams, lotions, drops and the like. For topicaladministrations, the compounds of this invention or theirphysiologically tolerated derivatives such as salts, esters, N-oxides,and the like are prepared and applied as solutions, suspensions, oremulsions in a physiologically acceptable diluent with or without apharmaceutical carrier.

Suitable dosage forms include but are not limited to oral, rectal,sub-lingual, mucosal, nasal, ophthalmic, subcutaneous, intramuscular,intravenous, transdermal, spinal, intrathecal, intra-articular,intra-arterial, sub-arachinoid, bronchial, lymphatic, and intra-uterileadministration, and other dosage forms for systemic delivery of activeingredients. In some embodiments, formulations suitable for oraladministration are preferred. In some applications, formulationssuitable for topical administration are preferred.

Topical Administration: In a typical embodiment, the compounds offormulas I-VII, IA-IB, and IIA-IIB are administered topically.

In one embodiment, the invention is directed to a topical pharmaceuticalcomposition comprising compound 17

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,polymorph, hydrate or any combination thereof, and a pharmaceuticallyacceptable carrier.

In one embodiment, the topical pharmaceutical composition is in the formof a solution, lotion, salve, cream, ointment, liposome, spray, gel,foam, roller stick, cleansing soap or bar, emulsion, mousse, aerosol,shampoo, or any combination thereof.

Topical administration is especially appropriate for hirsutism,alopecia, acne and excess sebum. The dose will vary, but as a generalguideline, the compound will be present in a dermatologically acceptablecarrier in an amount of from about 0.01 to 50 w/w %, and more typicallyfrom about 0.1 to 10 w/w %. Typically, the dermatological preparationwill be applied to the affected area from 1 to 4 times daily.“Dermatologically acceptable” refers to a carrier which may be appliedto the skin or hair, and which will allow the drug to diffuse to thesite of action. More specifically, it refers to a site where inhibitionof androgen receptor or degradation of androgen receptor is desired.

In a further embodiment, the compounds of formulas I-VII, IA-IB, andIIA-IIB are used topically to relieve alopecia, especially androgenicalopecia. Androgens have a profound effect on both hair growth and hairloss. In most body sites, such as the beard and pubic skin, androgensstimulate hair growth by prolonging the growth phase of the hair cycle(anagen) and increasing follicle size. Hair growth on the scalp does notrequire androgens but, paradoxically, androgens are necessary for thebalding on the scalp in genetically predisposed individuals (androgenicalopecia) where there is a progressive decline in the duration of anagenand in hair follicle size. Androgenic alopecia is also common in womenwhere it usually presents as a diffuse hair loss rather than showing thepatterning seen in men.

While the compounds of formulas I-VII, IA-IB, and IIA-IIB will mosttypically be used to alleviate androgenic alopecia, the invention is notlimited to this specific condition. The compounds of formulas I-VII,IA-IB, and IIA-IIB may be used to alleviate any type of alopecia.Examples of non-androgenic alopecia include alopecia areata, alopeciadue to radiotherapy or chemotherapy, scarring alopecia, stress relatedalopecia, etc. As used in this application “alopecia” refers to partialor complete hair loss on the scalp.

Thus, the compounds of formulas I-VII, IA-IB, and IIA-IIB can be appliedtopically to the scalp and hair to prevent, or alleviate balding.Further, the compound of formulas I-VII, IA-IB, and IIA-IIB can beapplied topically in order to induce or promote the growth or regrowthof hair on the scalp.

In a further embodiment of the invention, a compound of formulas I-VII,IA-IB, and IIA-IIB is applied topically in order to prevent the growthof hair in areas where such hair growth in not desired. One such usewill be to alleviate hirsutism. Hirsutism is excessive hair growth inareas that typically do not have hair (i.e., a female face). Suchinappropriate hair growth occurs most commonly in women and isfrequently seen at menopause. The topical administration of thecompounds of formulas I-VII, IA-IB, and IIA-IIB will alleviate thiscondition leading to a reduction, or elimination of this inappropriate,or undesired, hair growth.

The compounds of formulas I-VII, IA-IB, and IIA-IIB may also be usedtopically to decrease sebum production. Sebum is composed oftriglycerides, wax esters, fatty acids, sterol esters and squalene.Sebum is produced in the acinar cells of the sebaceous glands andaccumulates as these cells age. At maturation, the acinar cells lyse,releasing sebum into the luminal duct so that it may be deposited on thesurface of the skin.

In some individuals, an excessive quantity of sebum is secreted onto theskin. This can have a number of adverse consequences. It can exacerbateacne, since sebum is the primary food source for Propionbacterium acnes,the causative agent of acne. It can cause the skin to have a greasyappearance, typically considered cosmetically unappealing.

Formation of sebum is regulated by growth factors and a variety ofhormones including androgens. The cellular and molecular mechanism bywhich androgens exert their influence on the sebaceous gland has notbeen fully elucidated. However, clinical experience documents the impactandrogens have on sebum production. Sebum production is significantlyincreased during puberty, when androgen levels are their highest. Thus,the compounds of formulas IA-IB, and IIA-IIB inhibit the secretion ofsebum and thus reduce the amount of sebum on the surface of the skin.The compounds of formulas I-VII, IA-IB, and IIA-IIB can be used to treata variety of dermal diseases such as acne or seborrheic dermatitis.

In addition to treating diseases associated with excess sebumproduction, the compounds of formulas I-VII, IA-IB, and IIA-IIB can alsobe used to achieve a cosmetic effect. Some consumers believe that theyare afflicted with overactive sebaceous glands. They feel that theirskin is oily and thus unattractive. These individuals can utilize thecompounds of formulas I-VII, IA-IB, and IIA-IIB to decrease the amountof sebum on their skin. Decreasing the secretion of sebum will alleviateoily skin in individuals afflicted with such conditions.

The compounds of formulas I-VII, IA-IB, and IIA-IIB of this inventionwill typically be administered topically. As used herein, topical refersto application of the compounds of formulas IA-IB, and IIA-IIB (andoptional carrier) directly to the skin and/or hair. The topicalcomposition according to the present invention can be in the form ofsolutions, lotions, salves, creams, ointments, liposomes, sprays, gels,foams, roller sticks, and any other formulation routinely used indermatology.

Thus, a further embodiment relates to cosmetic or pharmaceuticalcompositions, in particular dermatological compositions, which compriseat least one of the compounds corresponding to formulas I-VII, IA-IB,and IIA-IIB above. Such dermatological compositions will contain from0.001% to 10% w/w % of the compounds in admixture with adermatologically acceptable carrier, and more typically, from 0.1 to 5w/w % of the compounds. Such compositions will typically be applied from1 to 4 times daily. The reader's attention is directed to Remington'sPharmaceutical Science, Edition 17, Mark Publishing Co., Easton, Pa. fora discussion of how to prepare such formulations.

The compositions according to the invention can also consist of solidpreparations constituting cleansing soaps or bars. These compositionsare prepared according to the usual methods.

The compounds of formulas I-VII, IA-IB, and IIA-IIB can also be used forthe hair in the form of aqueous, alcoholic or aqueous-alcoholicsolutions, or in the form of creams, gels, emulsions or mousses, oralternatively in the form of aerosol compositions also comprising apropellant under pressure. The composition according to the inventioncan also be a hair care composition, and in particular a shampoo, ahair-setting lotion, a treating lotion, a styling cream or gel, a dyecomposition, a lotion or gel for preventing hair loss, etc. The amountsof the various constituents in the dermatological compositions accordingto the invention are those conventionally used in the fields considered.

The medicinal and cosmetics containing the compounds of formulas I-VII,IA-IB, and IIA-IIB will typically be packaged for retail distribution(i.e., an article of manufacture). Such articles will be labeled andpackaged in a manner to instruct the patient how to use the product.Such instructions will include the condition to be treated, duration oftreatment, dosing schedule, etc.

Antiandrogens, such as finasteride or flutamide, have been shown todecrease androgen levels or block androgen action in the skin to someextent but suffer from undesirable systemic effects. An alternativeapproach is to topically apply a selective androgen receptor degrader(SARD) compound to the affected areas. In one embodiment, such a SARDcompound would exhibit potent but local inhibition of AR activity. Inanother embodiment, the SARD compound would exhibit potent but localdegradation of AR activity. In another embodiment, the SARD compoundwould not penetrate to the systemic circulation of the subject. Inanother embodiment, the SARD compound would be rapidly metabolized uponentry into the blood, limiting systemic exposure.

To prepare such pharmaceutical dosage forms, the active ingredient maybe mixed with a pharmaceutical carrier according to conventionalpharmaceutical compounding techniques. The carrier may take a widevariety of forms depending on the form of preparation desired foradministration.

As used herein “pharmaceutically acceptable carriers or diluents” arewell known to those skilled in the art. The carrier or diluent may be asolid carrier or diluent for solid formulations, a liquid carrier ordiluent for liquid formulations, or mixtures thereof.

Solid carriers/diluents include, but are not limited to, a gum, a starch(e.g. corn starch, pregeletanized starch), a sugar (e.g., lactose,mannitol, sucrose, dextrose), a cellulosic material (e.g.microcrystalline cellulose), an acrylate (e.g. polymethylacrylate),calcium carbonate, magnesium oxide, talc, or mixtures thereof.

Oral Administration and Parenteral:

In preparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed. Thus, for liquid oralpreparations, such as, for example, suspensions, elixirs and solutions,suitable carriers and additives include water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like. For solidoral preparations such as, for example, powders, capsules and tablets,suitable carriers and additives include starches, sugars, diluents,granulating agents, lubricants, binders, disintegrating agents and thelike. Due to their ease in administration, tablets and capsulesrepresent the most advantageous oral dosage unit form. If desired,tablets may be sugar coated or enteric coated by standard techniques.

For parenteral formulations, the carrier will usually comprise sterilewater, though other ingredients, for example, ingredients that aidsolubility or for preservation, may be included.

Injectable solutions may also be prepared in which case appropriatestabilizing agents may be employed.

In some applications, it may be advantageous to utilize the active agentin a “vectorized” form, such as by encapsulation of the active agent ina liposome or other encapsulant medium, or by fixation of the activeagent, e.g., by covalent bonding, chelation, or associativecoordination, on a suitable biomolecule, such as those selected fromproteins, lipoproteins, glycoproteins, and polysaccharides.

Treatment methods of the present invention using formulations suitablefor oral administration may be presented as discrete units such ascapsules, cachets, tablets, or lozenges, each containing a predeterminedamount of the active ingredient as, for example, a powder or granules.Optionally, a suspension in an aqueous liquor or a non-aqueous liquidmay be employed, such as a syrup, an elixir, an emulsion, or a draught.

A tablet may be made by compression or molding, or wet granulation,optionally with one or more accessory ingredients. Compressed tabletsmay be prepared by compressing in a suitable machine, with the activecompound being in a free-flowing form such as a powder or granules whichoptionally is mixed with, for example, a binder, disintegrant,lubricant, inert diluent, surface active agent, or discharging agent.Molded tablets comprised of a mixture of the powdered active compoundwith a suitable carrier may be made by molding in a suitable machine.

A syrup may be made by adding the active compound to a concentratedaqueous solution of a sugar, for example sucrose, to which may also beadded any accessory ingredient(s).

Such accessory ingredient(s) may include flavorings, suitablepreservative, agents to retard crystallization of the sugar, and agentsto increase the solubility of any other ingredient, such as apolyhydroxy alcohol, for example glycerol or sorbitol.

Formulations suitable for parenteral administration may comprise asterile aqueous preparation of the active compound, which preferably isisotonic with the blood of the recipient (e.g., physiological salinesolution). Such formulations may include suspending agents andthickening agents and liposomes or other microparticulate systems whichare designed to target the compound to blood components or one or moreorgans. The formulations may be presented in unit-dose or multi-doseform.

Parenteral administration may comprise any suitable form of systemicdelivery. Administration may for example be intravenous, intra-arterial,intrathecal, intramuscular, subcutaneous, intramuscular, intra-abdominal(e.g., intraperitoneal), etc., and may be affected by infusion pumps(external or implantable) or any other suitable means appropriate to thedesired administration modality.

Nasal and other mucosal spray formulations (e.g. inhalable forms) cancomprise purified aqueous solutions of the active compounds withpreservative agents and isotonic agents. Such formulations arepreferably adjusted to a pH and isotonic state compatible with the nasalor other mucous membranes. Alternatively, they can be in the form offinely divided solid powders suspended in a gas carrier. Suchformulations may be delivered by any suitable means or method, e.g., bynebulizer, atomizer, metered dose inhaler, or the like.

Formulations for rectal administration may be presented as a suppositorywith a suitable carrier such as cocoa butter, hydrogenated fats, orhydrogenated fatty carboxylic acids.

Transdermal formulations may be prepared by incorporating the activeagent in a thixotropic or gelatinous carrier such as a cellulosicmedium, e.g., methyl cellulose or hydroxyethyl cellulose, with theresulting formulation then being packed in a transdermal device adaptedto be secured in dermal contact with the skin of a wearer.

In addition to the aforementioned ingredients, formulations of thisinvention may further include one or more accessory ingredient(s)selected from, for example, diluents, buffers, flavoring agents,binders, disintegrants, surface active agents, thickeners, lubricants,preservatives (including antioxidants), and the like.

The formulations of the present invention can have immediate release,sustained release, delayed-onset release or any other release profileknown to one skilled in the art.

It is to be understood that this invention encompasses any embodiment ofa compound as described herein, which in some embodiments is referred toas “a compound of this invention”.

For administration to mammals, and particularly humans, it is expectedthat the physician will determine the actual dosage and duration oftreatment, which will be most suitable for an individual and can varywith the age, weight and response of the particular individual.

In one embodiment, the methods of this invention may compriseadministration of a compound of this invention at various dosages. Inone embodiment, a compound of this invention is administered at a dosageof 1-3000 mg per day. In additional embodiments, a compound of thisinvention is administered at a dose of 1-10 mg per day, 3-26 mg per day,3-60 mg per day, 3-16 mg per day, 3-30 mg per day, 10-26 mg per day,15-60 mg, 50-100 mg per day, 50-200 mg per day, 100-250 mg per day,125-300 mg per day, 20-50 mg per day, 5-50 mg per day, 200-500 mg perday, 125-500 mg per day, 500-1000 mg per day, 200-1000 mg per day,1000-2000 mg per day, 1000-3000 mg per day, 125-3000 mg per day,2000-3000 mg per day, 300-1500 mg per day or 100-1000 mg per day. In oneembodiment, a compound of this invention is administered at a dosage of25 mg per day. In one embodiment, a compound of this invention isadministered at a dosage of 40 mg per day. In one embodiment, a compoundof this invention is administered at a dosage of 50 mg per day. In oneembodiment, a compound of this invention is administered at a dosage of67.5 mg per day. In one embodiment, a compound of this invention isadministered at a dosage of 75 mg per day. In one embodiment, a compoundof this invention is administered at a dosage of 80 mg per day. In oneembodiment, a compound of this invention is administered at a dosage of100 mg per day. In one embodiment, a compound of this invention isadministered at a dosage of 125 mg per day. In one embodiment, acompound of this invention is administered at a dosage of 250 mg perday. In one embodiment, a compound of this invention is administered ata dosage of 300 mg per day. In one embodiment, a compound of thisinvention is administered at a dosage of 500 mg per day. In oneembodiment, a compound of this invention is administered at a dosage of600 mg per day. In one embodiment, a compound of this invention isadministered at a dosage of 1000 mg per day. In one embodiment, acompound of this invention is administered at a dosage of 1500 mg perday. In one embodiment, a compound of this invention is administered ata dosage of 2000 mg per day. In one embodiment, a compound of thisinvention is administered at a dosage of 2500 mg per day. In oneembodiment, a compound of this invention is administered at a dosage of3000 mg per day. In another embodiment, the compound is any one ofcompounds 13-21, 49, 50 and 17a.

In one embodiment, the methods of this invention may compriseadministration of a compound of this invention at various dosages. Inone embodiment, a compound of this invention is administered at a dosageof 3 mg. In additional embodiments, a compound of this invention isadministered at a dosage of 10 mg, 30 mg, 40 mg, 50 mg, 80 mg, 100 mg,120 mg, 125 mg, 200 mg, 250 mg, 300 mg, 450 mg, 500 mg, 600 mg, 900 mg,1000 mg, 1500 mg, 2000 mg, 2500 mg or 3000 mg. In another embodiment,the compound is any one of compounds 13-21, 49, 50 and 17a.

In one embodiment, the methods of this invention may compriseadministration of a compound of this invention at various dosages. Inone embodiment, a compound of this invention is administered at a dosageof 0.1 mg/kg/day. In additional embodiments, a compound of thisinvention is administered at a dosage between 0.2 to 30 mg/kg/day, or0.2 mg/kg/day, 0.3 mg/kg/day, 1 mg/kg/day, 3 mg/kg/day, 5 mg/kg/day, 10mg/kg/day, 20 mg/kg/day, 30 mg/kg/day, 50 mg/kg/day or 100 mg/kg/day.

In one embodiment, the methods of this invention provide for the use ofa pharmaceutical composition comprising a compound of formulas I-VII,IA-IB, and IIA-IIB. In additional embodiments, the methods of thisinvention are provided for use of a pharmaceutical compositioncomprising a compound of formula I, formula IA, formula IB, formula II,formula IIA, formula IIB, formula III, formula IV, or formula V, formulaVI, or formula VII, or any one of compounds 13-21, 49, 50 and 17a.

In certain embodiment, the pharmaceutical composition is a solid dosageform. In another embodiment, the pharmaceutical composition is a tablet.In another embodiment, the pharmaceutical composition is a capsule. Inanother embodiment, the pharmaceutical composition is a solution. Inanother embodiment, the pharmaceutical composition is a transdermalpatch.

In one embodiment, use of a compound of this invention or a compositioncomprising the same, will have utility in inhibiting, suppressing,enhancing or stimulating a desired response in a subject, as will beunderstood by one skilled in the art. In another embodiment, thecompositions may further comprise additional active ingredients, whoseactivity is useful for the particular application for which the compoundof this invention is being administered.

For administration to mammals, and particularly humans, it is expectedthat the physician will determine the actual dosage and duration oftreatment, which will be most suitable for an individual and can varywith the age, weight, genetics and/or response of the particularindividual.

In some embodiments, any of the compositions of this invention willcomprise a compound of this invention, in any form or embodiment asdescribed herein. In some embodiments, any of the compositions of thisinvention will consist of a compound of this invention, in any form orembodiment as described herein. In some embodiments, of the compositionsof this invention will consist essentially of a compound of thisinvention, in any form or embodiment as described herein. In someembodiments, the term “comprise” refers to the inclusion of theindicated active agent, such as the compound of this invention, as wellas inclusion of other active agents, and pharmaceutically acceptablecarriers, excipients, emollients, stabilizers, etc., as are known in thepharmaceutical industry. In some embodiments, the term “consistingessentially of” refers to a composition, whose only active ingredient isthe indicated active ingredient, however, other compounds may beincluded which are for stabilizing, preserving, etc. the formulation,but are not involved directly in the therapeutic effect of the indicatedactive ingredient. In some embodiments, the term “consisting essentiallyof” may refer to components which facilitate the release of the activeingredient. In some embodiments, the term “consisting” refers to acomposition, which contains the active ingredient and a pharmaceuticallyacceptable carrier or excipient.

It is to be understood that any use of any of the compounds as hereindescribed may be used in the treatment of any disease, disorder orcondition as described herein, and represents an embodiment of thisinvention. In one embodiment, the compounds are a free base, free acid,non-charged or non-complexed compound.

The following examples are presented in order to more fully illustratethe preferred embodiments of the invention. They should in no way,however, be construed as limiting the broad scope of the invention.

EXAMPLES Example 1 Synthesis of (S)-3-(Substituted phenylamino)-N-(4-nitro- or 4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamides (Compounds 12-19)

(2R)-1-Methacryloylpyrrolidin-2-carboxylic acid (2)

D-Proline (14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOH andcooled in an ice bath. The resulting alkaline solution was diluted withacetone (71 mL). An acetone solution (71 mL) of methacryloyl chloride(13.56 g, 0.13 mol) and 2 N NaOH solution (71 mL) were simultaneouslyadded over 40 min to the aqueous solution of D-proline in an ice bath.The temperature of the mixture was kept at 10-11° C. during the additionof the methacryloyl chloride. After stirring (3 h, room temperature(RT)), the mixture was evaporated in vacuo at a temperature at 35-45° C.to remove acetone. The resulting solution was washed with ethyl etherand was acidified to pH 2 with concentrated HCl. The acidic mixture wassaturated with NaCl and was extracted with EtOAc (100 mL×3). Thecombined extracts were dried over Na₂SO₄, filtered through Celite®, andevaporated in vacuo to give the crude product as a colorless oil.Recrystallization of the oil from ethyl ether and hexanes afforded 16.2g (68%) of the desired compound as colorless crystals: mp 102.1-103.4°C. (lit. mp 102.5-103.5° C.); the NMR spectrum of this compounddemonstrated the existence of two rotamers of the title compound.

¹H NMR (300 MHz, DMSO-d₆) δ 5.28 (s) and 5.15 (s) for the first rotamer,5.15 (s) and 5.03 (s) for the second rotamer (totally 2H for bothrotamers, vinyl CH₂), 4.48-4.44 for the first rotamer, 4.24-4.20 (m) forthe second rotamer (totally 1H for both rotamers, CH at the chiralcenter), 3.57-3.38 (m, 2H, CH₂), 2.27-2.12 (1H, CH), 1.97-1.72 (m, 6H,CH₂, CH, Me); ¹³C NMR (75 MHz, DMSO-d₆) δ for major rotamer 173.3,169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437(OH), 1737 (C═O), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178cm-1; [α]_(D) ²⁶ +80.8° (c=1, MeOH); Anal. Calcd. for C₉H₁₃NO₃: C,59.00, H, 7.15, N, 7.65. Found: C, 59.13, H, 7.19, N, 7.61.

(3R,8aR)-3-Bromomethyl-3-methyl-tetrahydro-pyrrolo[2,1-c][1,4]oxazine-1,4-dione(3)

A solution of NBS (23.5 g, 0.132 mol) in 100 mL of DMF was addeddropwise to a stirred solution of the (methyl-acryloyl)-pyrrolidine(16.1 g, 88 mmol) in 70 mL of DMF under argon at RT, and the resultingmixture was stirred 3 days. The solvent was removed in vacuo, and ayellow solid was precipitated. The solid was suspended in water, stirredovernight at RT, filtered, and dried to give 18.6 g (81%) (smallerweight when dried ˜34%) of the title compound as a yellow solid: mp158.1-160.3° C.;

¹H NMR (300 MHz, DMSO-d₆) δ 4.69 (dd, J=9.6 Hz, J=6.7 Hz, 1H, CH at thechiral center), 4.02 (d, J=11.4 Hz, 1H, CHHa), 3.86 (d, J=11.4 Hz, 1H,CHHb), 3.53-3.24 (m, 4H, CH₂), 2.30-2.20 (m, 1H, CH), 2.04-1.72 (m, 3H,CH₂ and CH), 1.56 (s, 2H, Me); ¹³C NMR (75 MHz, DMSO-d₆) δ 167.3, 163.1,83.9, 57.2, 45.4, 37.8, 29.0, 22.9, 21.6; IR (KBr) 3474, 1745 (C═O),1687 (C═O), 1448, 1377, 1360, 1308, 1227, 1159, 1062 cm⁻¹; [α]D²⁶+124.5° (c=1.3, chloroform); Anal. Calcd. for C₉H₁₂BrNO₃: C, 41.24, H,4.61, N, 5.34. Found: C, 41.46, H, 4.64, N, 5.32.

(2R)-3-Bromo-2-hydroxy-2-methylpropanoic acid (4)

A mixture of bromolactone (18.5 g, 71 mmol) in 300 mL of 24% HBr washeated at reflux for 1 h. The resulting solution was diluted with brine(200 mL), and was extracted with ethyl acetate (100 mL×4). The combinedextracts were washed with saturated NaHCO₃ (100 mL×4). The aqueoussolution was acidified with concentrated HCl to pH=1, which, in turn,was extracted with ethyl acetate (100 mL×4). The combined organicsolution was dried over Na₂SO₄, filtered through Celite®, and evaporatedin vacuo to dryness. Recrystallization from toluene afforded 10.2 g(86%) of the desired compound as colorless crystals: mp 110.3-113.8° C.;

¹H NMR (300 MHz, DMSO-d₆) δ 3.63 (d, J=10.1 Hz, 1H, CHHa), 3.52 (d,J=10.1 Hz, 1H, CHHb), 1.35 (s, 3H, Me); IR (KBr) 3434 (OH), 3300-2500(COOH), 1730 (C═O), 1449, 1421, 1380, 1292, 1193, 1085 cm⁻¹; [α]D²⁶+10.5° (c=2.6, MeOH); Anal. Calcd. for C₄H₇BrO₃: C, 26.25, H, 3.86.Found: C, 26.28, H, 3.75.

(2R)-3-Bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide(8)

Thionyl chloride (46.02 g, 0.39 mol) was added dropwise to a cooledsolution (less than 4° C.) of (R)-3-bromo-2-hydroxy-2-methylpropanoicacid (51.13 g, 0.28 mol) in 300 mL of THF under an argon atmosphere. Theresulting mixture was stirred for 3 h under the same condition. To thiswas added Et₃N (39.14 g, 0.39 mol) and stirred for 20 min under the samecondition. After 20 min, 5-amino-2-cyanobenzotrifluoride (40.0 g, 0.21mol), 400 mL of THF were added and then the mixture was allowed to stirovernight at RT. The solvent was removed under reduced pressure to givea solid which was treated with 300 mL of H₂O, extracted with EtOAc(2×400 mL). The combined organic extracts were washed with saturatedNaHCO₃ solution (2×300 mL) and brine (300 mL). The organic layer wasdried over MgSO₄ and concentrated under reduced pressure to give a solidwhich was purified from column chromatography using CH₂Cl₂/EtOAc (80:20)to give a solid. This solid was recrystallized from CH₂Cl₂/hexane togive 55.8 g (73.9%) of(2R)-3-bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamideas a light-yellow solid. Mp 134.0-136.5° C.;

¹H NMR (CDCl₃/TMS) δ 1.66 (s, 3H, CH₃), 3.11 (s, 1H, OH), 3.63 (d,J=10.8 Hz, 1H, CH₂), 4.05 (d, J=10.8 Hz, 1H, CH₂), 7.85 (d, J=8.4 Hz,1H, ArH), 7.99 (dd, J=2.1, 8.4 Hz, 1H, ArH), 8.12 (d, J=2.1 Hz, 1H,ArH), 9.04 (bs, 1H, NH). MS (ESI) 349.0 [M-H]⁻; M.p.: 124-126° C.

Preparation of 4-Cyano 2,3-Substituted Anilines (26-28)

General Procedure I:

Arylaniline 24 (4.46 mmol), boric acid 25 (4.46 mmol), Pd cat (0.224mmol, the structure as shown in Scheme 2) and K₂PO₄ (8.92 mmol) in 10 mLof 1,4-dioxane were heated to reflux under argon overnight. The mixturewas cooled to RT and poured into DCM, which was washed with water, driedover anhydrous MgSO₄, and evaporated to dryness. The mixture waspurified with flash column chromatography as an eluent EtOAc/hexane andthen the condensed compounds were then recrystallized at EtOAc/hexane togive the target products (26˜28).

5-Amino-[1,1′-biphenyl]-2-carbonitrile (26)

Yield 80%; Brown solid; MS (ESI) 192.8 [M-H]⁻; 217.1 [M+Na]⁺; ¹H NMR(CDCl₃, 400 MHz) δ 7.54-7.42 (m, 6H), 6.71 (d, J=3.2 Hz, 1H), 6.66 (dd,J=11.2, 3.2 Hz, 1H), 4.22 (bs, 2H, NH₂).

6-Amino-[1,1′-biphenyl]-3-carbonitrile (27)

Yield 79%; Brown solid; MS (ESI) 192.8 [M-H]⁻; 217.1 [M+Na]⁺; ¹H NMR(CDCl₃, 400 MHz) δ 7.50-7.30 (m, 7H), 6.76 (dd, J=11.2, 6.0 Hz, 1H),4.27 (bs, 2H, NH₂).

5-Amino-4′-fluoro-[1,1′-biphenyl]-2-carbonitrile (28)

Yield 98%; Brown solid; MS (ESI) 200.8 [M-H]⁻; ¹H NMR (DMSO-d₆, 400 MHz)δ 7.50-7.48 (m, 3H), 7.34-7.30 (m, 2H), 6.63 (m, 2H), 6.26 (bs, 2H,NH₂).

Preparation of Several 2-hydroxy-2-methylpropanamides (12-19)

General Procedure II:

Step 1.

Preparation of(S)—N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyloxirane-2-carboxamide(10) in THF: a mixture of hydroxylbromide 8 (1.0 g, 2.84 mmol) andpotassium carbonate (790 mg, 5.70 mmol) in 60 mL acetone was heated toreflux for 30 min. After complete conversion of starting bromide 8 todesired epoxide 10 as monitored by TLC, the solvent was evaporated underreduced pressure to give yellowish residue, which was poured into 20 mLof anhydrous EtOAc. The solution was filtered through Celite® pad toremove K₂CO₃ residue and condensed under reduced pressure to give ayellowish solid of epoxide 10, which was dissolved in 5 mL of anhydrousTHF to prepare a solution of epoxide 10 in THF. The resulting solutionwas directly used as next reactant without analysis.

Step 2.

NaH of 60% dispersion in mineral oil (228 mg, 5.7 mmol) was added in 30mL of anhydrous THF solvent in 100 mL dried two necked round bottomflask equipped with a dropping funnel. Substituted aniline 11 (2.84mmol) was added to the solution under argon atmosphere at ice-waterbath, and the resulting solution was stirred for 30 min at the ice-waterbath. Into the flask, the prepared solution of epoxide 9 or 10 (2.84mmol in THF) was added through dropping funnel under argon atmosphere atthe ice-water bath and stirred overnight at RT. After adding 1 mL ofH₂O, the reaction mixture was condensed under reduced pressure, and thendispersed into 50 mL of EtOAc, washed with 50 mL (×2) water, brine,dried over anhydrous MgSO₄, and evaporated to dryness. The mixture waspurified with flash column chromatography with EtOAc/hexane as eluent,and then the condensed compounds were then recrystallized atEtOAc/hexane to give the respective target products 12-19.

Preparation of SARDs 12-19

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-((4-cyanophenyl)amino)-2-hydroxy-2-methylpropanamide(12)

Yield 58%; Brown solid; MS (ESI) 387.2 [M-H]⁻; ¹H NMR (DMSO-d₆, 400 MHz)δ 10.42 (bs, 1H, NH), 8.11 (s, 1H), 8.21 (d, J=2.2 Hz, 1H), 8.01 (d,J=2.2 Hz, 1H), 7.38 (d, J=8.7, 2H), 6.75 (d, J=8.7 Hz, 2H), 6.12 (bs,1H, NH), 3.61 (m, 1H), 3.25 (m, 1H), 2.29 (bs, 1H, OH), 1.42 (s, 3H);Anal. Calcd for C₁₉H₁₅F₃N₄O₂: C, H, N.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-((4-cyanonaphthalen-1-yl)amino)-2-hydroxy-2-methylpropanamide(13)

Yield 39%; Brown solid; MS (ESI) 437.2 [M-H]⁻; ¹H NMR (CDCl₃, 400 MHz) δ9.14 (bs, 1H, NH), 8.15 (d, J=8.3 Hz, 1H), 8.06 (d, J=1.8 Hz, 1H), 7.98(dd, J=8.3, 1.8 Hz, 1H), 7.82-7.71 (m, 5H), 6.70 (d, J=8.1 Hz, 1H), 5.51(bs, 1H, NH), 3.95 (m, 1H), 3.57 (m, 1H), 2.29 (bs, 1H, OH), 1.74 (s,3H); Anal. Calcd for C₂₃H₁₇F₃N₄O₂: C, H, N.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-((6-cyano-[1,1′-biphenyl]-3-yl)amino)-2-hydroxy-2-methylpropanamide(14)

Yield 42%; Brown solid; MS (ESI) 463.0 [M-H]⁻; ¹H NMR (DMSO-d₆, 400 MHz)δ 10.50 (bs, 1H, NH), 8.46 (d, J=2.0 Hz, 1H), 8.17 (dd, J=8.4, 2.0 Hz,1H), 8.08 (d, J=8.4 Hz, 1H), 7.47 (m, 6H), 6.75 (m, 1H), 6.58 (m, 1H),6.13 (bs, 1H, NH), 3.67 (d, J=14.8 Hz, 1H), 3.31 (d, J=14.8 Hz, 1H),2.49 (bs, 1H, OH), 1.24 (s, 3H); Anal. Calcd for C₂₅H₁₉F₃N₄O₂: C, H, N.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-((5-cyano-[1,1′-biphenyl]-2-yl)amino)-2-hydroxy-2-methylpropanamide(15)

Yield 32%; Brown solid; MS (ESI) 462.9 [M-H]⁻; 487.1 [M+Na]⁺; ¹H NMR(CDCl₃, 400 MHz) δ 10.49 (bs, 1H, NH), 8.45 (m, 1H), 8.17-7.43 (m, 7H),7.23 (m, 2H), 6.52 (m, 1H), 6.18 (bs, 1H, NH), 3.67 (d, J=14.8 Hz, 1H),3.31 (d, J=14.8 Hz, 1H), 2.47 (bs, 1H, OH), 1.23 (s, 3H); Anal. Calcdfor C₂₅H₁₉F₃N₄O₂: C, H, N.

General Procedure III:

A mixture of compounds 12 or 14 (0.15 mmol) and 0.5 mL of alkylhalide(methyl iodide, n-propylbromide or benzyl bromide) with 1 mL ofN,N-diisopropylethylamine (DIPEA, Hünig's base) was loaded into a vesselwith a cap. The reaction vessels were placed in a reactor block in themicrowave. A programmable microwave irradiation cycle of 30 min on (300W) at 150° C. and 25 min off (fan-cooled) was executed (irradiationtime, 30 min). The mixture was transferred to round bottom flask to beconcentrated under reduced pressure and poured into EtOAc, which waswashed with water and dried over anhydrous MgSO₄, concentrated, purifiedby silica gel chromatography (EtOAc/n-hexane) to afford to desiredproducts (17, 17a, 18 and 19).

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-((6-cyano-[1,1′-biphenyl]-3-yl)(methyl)amino)-2-hydroxy-2-methylpropanamide(17)

Yield 42%; Yellowish solid; MS (ESI) 501.1 [M+Na]⁺; ¹H NMR (CDCl₃, 400MHz) δ 9.09 (bs, 1H, NH), 8.06 (s, 1H), 7.93 (d, J=2.0 Hz, 1H), 7.90 (d,J=2.0 Hz, 1H), 7.79-7.28 (m, 7H), 6.88 (m, 2H), 3.98 (d, J=15.6 Hz, 1H),3.75 (d, J=15.6 Hz, 1H), 3.01 (s, 3H), 2.06 (s, 1H, OH), 1.63 (s, 3H);Anal. Calcd for C₂₆H₂₁F₃N₄O₂: C, H, N.

(S)-3-(Benzyl(4-cyanophenyl)amino)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide(18)

Yield 32%; Brown solid; MS (ESI) 476.9 [M-H]⁻; 501.1 [M+Na]⁺; ¹H NMR(CDCl₃, 400 MHz) δ 10.22 (bs, 1H, NH), 8.35 (s, 1H), 8.17 (d, J=8.2 Hz,1H), 8.08 (d, J=8.2 Hz, 1H), 7.20-7.11 (m, 5H), 6.75 (m, 1H), 6.91 (m,2H), 6.23 (s, 1H), 4.90 (s, 2H), 3.99 (d, J=14.8 Hz, 1H), 3.89 (d,J=14.8 Hz, 1H), 3.42 (bs, 1H, OH), 1.41 (s, 3H); Anal. Calcd forC₂₆H₂₁F₃N₄O₂: C, H, N.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-((6-cyano-4′-fluoro-[1,1′-biphenyl]-3-yl)(methyl)amino)-2-hydroxy-2-methylpropanamide(19)

Yield 38%; Brown solid; MS (ESI) 495.2 [M-H]⁻; ¹H NMR (CDCl₃, 400 MHz) δ10.17 (bs, 1H, NH), 8.15 (s, 1H), 8.00 (d, J=2.0 Hz, 1H), 8.08 (d, J=2.0Hz, 1H), 7.49-7.48 (m, 4H), 7.34-7.30 (m, 2H), 6.75 (m, 1H), 3.99 (d,J=14.8 Hz, 1H), 3.79 (d, J=14.8 Hz, 1H), 3.09 (s, 3H), 2.11 (bs, 1H,OH), 1.61 (s, 3H); Anal. Calcd for C₂₆H₂₀F₄N₄O₂: C, H, N.

Example 1A Synthesis of Compounds 14 and 17

Synthetic Scheme of SARDs 14 and 17

Scheme 5.

Preparation of SARDs 14 and 17. Reagents and conditions: (a) NaH, THF,0° C.˜RT; (b) CH₃I, N,N-diisopropylethylamine, 120° C., MW.

Hydroxybromide 8 was used as an important intermediate which was reactedwith aniline 26 after activating by NaH in THF solvent to produce 14.N-Alkylation of 14 was a microwave assisted reaction and performed undera basic conditions in using N,N-diisopropylethylamine (Hünig's base) togenerate 17.

Example 1B Synthesis of Compounds 49 and 50

General Procedure:

Preparation of Compounds 49 and 50

A mixture of phenyl trifluoromethanesulfonate (500 mg, 2.21 mmol),palladium acetate (II) (50 mg, 0.22 mmol), (±)2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (317 mg, 0.66 mmol) andcesium carbonate (1.09 g, 3.31 mmol) in 50 mL of toluene were inertizedwith argon. Then, 4-nitroaniline (331 mg, 2.43 mmol) or 4-fluoroaniline(2.43 mmol) was added and the mixture was heated at 110° C. overnight.The reaction mixture was allowed to cool to room temperature andfiltered through a pad of Celite®. The filtrate was diluted with CH₂Cl₂and water. The phases were separated and the aqueous phase wasre-extracted 2 times with CH₂Cl₂. The combined organic phases were driedover Na₂SO₄ and the resulting solution was dried over anhydrous Na₂SO₄and purified with flash column chromatography as an eluent EtOAc/hexane(1/6, v/v) to give 4-nitro-N-phenylaniline or 4-fluoro-N-phenylaniline.

NaH of 60% dispersion in mineral oil (228 mg, 5.7 mmol) was added in 20mL of anhydrous THF solvent into a 100 mL dried two necked round bottomflask equipped with a dropping funnel and NH(Ph)(Ar) [Ar=4-fluorophenyl;4-nitrophenyl] (2.84 mmol) was added to the solution under argonatmosphere in ice-water bath, and the resulting solution was stirred for30 min at the ice-water bath. Into the flask, epoxide 10 (2.84 mmol inTHF) was added through dropping funnel under argon atmosphere at theice-water bath and stirred overnight at room temperature. After adding 1mL of H₂O, the reaction mixture was condensed under reduced pressure,and then dispersed into 50 mL of EtOAc, washed with 50 mL (×2) water,brine, dried over anhydrous MgSO₄, and evaporated to dryness. Themixture was purified with flash column chromatography as an eluentEtOAc/hexane, and then the condensed compounds were then recrystallizedin EtOAc/hexane to give a target product 49 or 50.

(S)—N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(4-fluorophenyl)(phenyl)amino)-2-hydroxy-2-methylpropanamide(49)

Yield; 67%; MS (ESI) m/z 456.1 [M-H]⁻; ¹H NMR (400 MHz, CDCl₃) δ 8.85(bs, 1H, NH), 7.87 (m, 1H), 7.81-7.73 (m, 2H), 7.65 (dd, J=8.4, 1.8 Hz,1H), 7.20 (m, 2H), 7.05-7.00 (m, 2H), 6.94-6.89 (m, 5H), 4.54 (d, J=15.2Hz, 1H), 3.84 (d, J=15.2 Hz, 1H), 3.61 (s, 1H), 1.53 (s, 3H).

Example 2 Novel AR Antagonists

The target of this research is:

-   -   (a) To synthesize and optimize orally bioavailable SARDs, and        deduce structure-activity relationship (SAR).    -   (b) Characterize SARDs in vitro in AR ligand binding,        transactivation, and AR degradation and proliferation assays in        PCa cells that are dependent on AR-FL and AR-SV for growth.    -   (c) Determine the pharmacokinetic (PK) properties, develop        appropriate formulation, and characterize SARDs in vivo in LNCaP        and 22RV-1 androgen-dependent and CRPC PCa xenografts,        respectively.

The preliminary results are generated with two lead molecules, compounds17 and 14, selected from a library.

Several molecules were synthesized and characterized with the intentionto develop next generation AR antagonists. Interestingly, several ofthese AR antagonists exhibited degradation activity at concentrationscomparable to their binding and antagonistic activity. These resultsprovided an impetus to explore the degradation activity of thesemolecules.

TABLE 1 SARDs of this invention, binding and AR antagonistic activitiesX R₁ R₂ K_(i) (nM) DHT n/a n/a n/a 6.62 MDV-3100 n/a n/a n/a 1075.3bicalutamide SO₂ F H 545.5 Cmpd 17 N(CH₃) CN phenyl 148.7 Cmpd 14 NH CNphenyl 198.5 Transcriptional Activation (Antagonist Mode) Wildtype W741Lbinding IC₅₀ % inhibition % inhibition Compound K_(i) (nM) (nM) at 1 μMIC₅₀ (nM) at 1 μM DHT 5.85 bicalutamide 545.5 420 91 — — MDV-3100 1075.3489 93 939 53 ARN-509 297 1939.4 ASC-J9 1008 3487.6 14 198.5 77 92 >100048 17 270.7 95 98 101.7 87

TABLE 2 DMPK Transcriptional Activation (mouse liver Wt. W741L T877Amicrosomes) Binding IC₅₀ IC₅₀ IC₅₀ T_(1/2) (min) Compound K_(i) (nM)(nM) (nM) (nM) CL_(int) (ml/min/kg) DHT 1 Bicalutamide 545.5 420 — 557Enzalutamide 1075.3 489 939 331.94 ARN-509 297.0 1939.4 390.52 ASC-J91008 3487.6 14 198.5 77 >1000 48 See Example 6 17 28.4 95 101.7 153.51See Example 6 49 275.41 172.22 5.069 min 136.8 ml/min/mg^(#) ^(#)see MLMmethod below:

Metabolism Studies with Mouse Liver Microsomes (MLM)

Objective:

To determine the relative stability of SARDs to metabolism by livermicrosomal enzyme using MLM.

Method:

Determination of metabolic stability (in vitro CL_(int)) of testcompounds with regard to Phase I and Phase I+II metabolic pathways.

Metabolic Stability to Phase I Pathways:

The assay was done in a final volume of 0.5 ml in duplicates (n=2). Testcompound (1 μM) was pre-incubated for 10 minutes at 37° C. in 100 mMTris-HCl, pH 7.5 containing 0.5 mg/ml liver microsomal protein. Afterpre-incubation, reaction was started by addition of 1 mM NADPH(pre-incubated at 37° C.). Incubations were carried out in triplicateand at various time-points (0, 5, 10, 15, 30 and 60 minutes), 100 μlaliquots were removed and quenched with 100 μl of acetonitrilecontaining internal standard. Samples were vortex mixed and centrifugedat 4000 rpm for 10 minutes. The supernatants were transferred to 96 wellplates and submitted for LC-MS/MS analysis. As control, sampleincubations done in absence of NADPH were also included. From % PCR (%Parent Compound Remaining), rate of compound disappearance is determined(slope) and in vitro CL_(int) (μl/min/mg protein) was calculated.

Metabolic Stability in Phase I & Phase II Pathways:

In this assay, test compound was incubated with liver microsomes anddisappearance of drug was determined using discovery grade LC-MS/MS. Tostimulate Phase II metabolic pathway (glucuronidation), UDPGA andalamethicin (a pore-forming peptide to increase microsomal activity)were included in the assay.

LC-MS/MS Analysis:

The analysis of the compounds under investigation was performed usingLC-MS/MS system consisting of Agilent 1100 HPLC with an MDS/Sciex 4000Q-Trap™ mass spectrometer. The separation was achieved using a C₁₈analytical column (Alltima™ 2.1×100 mm, 3 μm) protected by a C₁₈ guardcartridge system (SecurityGuard™ ULTRA Cartridges UHPLC for 4.6 mm IDcolumns, Phenomenex). Mobile phase was consisting of channel A (95%acetonitrile+5% water+0.1% formic acid) and channel C (95% water+5%acetonitrile+0.1% formic acid) and was delivered at a flow rate of 0.4mL/min. The volume ratio of acetonitrile and water was optimized foreach of the analytes. Multiple reaction monitoring (MRM) scans were madewith curtain gas, collision gas, nebulizer gas, and auxiliary gasoptimized for each compound, and source temperature at 550° C. Molecularions were formed using an ion spray voltage (IS) of −4200 V (negativemode). Declustering potential (DP), entrance potential (EP), collisionenergy (CE), product ion mass, and cell exit potential (CXP) wereoptimized for each compound.

As shown in Table 1, the first-generation SARDs were generated withamino linkers. Their binding and AR antagonistic activities werecompared to standard molecules such as bicalutamide, enzalutamide(MDV3100), ARN-509, and ASC-J9.

As shown in Table 1 and Table 2, the SARDs of the invention bound to ARwith higher affinity than the reference standards. Interestingly, twomolecules in the list, compounds 14 and 17 robustly bound to AR bydisplacing the radiolabeled mibolerone from LBD in an AR-LBD bindingassay. They bound at a much higher affinity than the referencestandards. Consistent with potent binding, the two molecules effectivelyantagonized the R1881 stimulated wild type AR transcriptional activityby potencies at least five-fold greater than MDV-3100 and bicalutamide(77 nM and 95 nM for 14 and 17, respectively, compared to 420 nM and 489nM for bicalutamide and MDV-3100, respectively) (Table 1 and Table 2).

Bicalutamide is a known agonist of AR containing W741L mutation, whereasMDV-3100 retains antagonist activity though its potency is somewhatreduced (939 nM). While 14 demonstrated reduced effectiveness in theW741L mutant (>1 μM), 17 retained the ability to antagonize agonistactivated W741L AR (101.7 nM). The W741L mutation was selected due tothe structural similarity of SARDs to bicalutamide (aryl propanamide).The antagonist activity of 17 was selective for the AR and did notcross-react with progesterone receptor (PR), mineralocorticoid receptor(MR) or glucocorticoid receptors (GR) (data not shown).

TABLE 3

WT Agonist WT Antagonist EC₅₀ % inhibition Compound X R₁ R₂ R₃ RBA (nM)E_(max) (nM) IC₅₀ (nM) at 1 μM S-22 O CN H H 5.8 ± 1.8 1.4  140 ± 15.1NA NA Bicalutamide SO₂ F H H 0.62 ± 0.06 NA NA 22.4 ± 6.7  90.9 ± 0.8312 NH CN H H 0.16 ± 0.01 626   156 ± 213.4 119 89.9 ± 0.4 13 NH CN—(CH)₄—  1.5 ± 0.05 >1000 48.3 ± 7.4  193 63.0 ± 1.2 14 NH CN Ph H 0.56± 0.03 NA NA 20.5 88.2 ± 1.1 15 NH CN H Ph 0.65 ± 0.06 >1000 22.6 ± 6.4 81.3 92.2 ± 1.0 18 NCH₂(C₆H₆) CN H H ND NA NA 118.6 92.7 ± 1.8 17 NCH₃CH Ph H NA NA 6 94.8

TABLE 4 W741L W741L T877A T877A Agonist Antagonist Agonist AntagonistEC₅₀ E_(max) IC₅₀ % inhibition EC₅₀ E_(max) IC₅₀ % inhibition Compound XR₁ R₂ R₃ (nM) (nM) (nM) at 1 μM (nM) (nM) (nM) at 1 μM Bicalutamide SO₂F H H 1.1 ± 3.4  273 ± 37.9 NA NA NA NA 229 73.7 ± 7.4 12 NH CN HH >1000 24.8 ± 7.2 >1000 20.9 ± 9.1  47  122 ± 26.4 NA NA 13 NH CN—(CH)₄— 2.4  93.1 ± 10.8 NA NA 3.4 56.1 ± 9.9 784.4 60.5 ± 7.8 14 NH CNPh H >1000 26.8 ± 1.6 >1000 48.3 ± 4.7  >1000 20.6 ± 3.6 79.1 85.6 ± 2.015 NH CN H Ph 1.9  76.7 ± 15.1 305 63.8 ± 13.8 >1000 18.6 ± 0.1 34.394.0 ± 0.7 18 NCH₂(C₆H₆) CN H H >1000 26.1 ± 1.7 >1000 47.6 ± 10.0 >100017.4 ± 5.4 470 74.8 ± 8.7 17 NCH₃ CH Ph H NA NA 101.7 87 NA NA 33.1 95.6

In general, compounds 12-21 acted as antagonists of wildtype androgenreceptor (wt-AR) with some residual agonism for 12, 13, and 15. Notably,17 was the most potent antagonist with an IC₅₀ value of 6 nM (Table 3).Mutant AR's W741L and T877A confer resistance to bicalutamide andhydroxyflutamide, respectively. Most of the compounds 12-21 displayedmixed agonist/antagonist activity in in vitro transcriptional activationassays. However, 17 retains potent pure antagonism in wildtype and bothmutations (Table 3 and Table 4), demonstrating potential to overcomeresistance to bicalutamide and/or hydroxyflutamide, independent of itsSARD activity (described below). 14 also demonstrated antagonistactivity in wildtype and mutant AR's, but was not a potent antagonist inall the mutants tested.

AR transactivation assay was performed with wildtype, W741L, and T877AAR constructs. W741 mutation to leucine or cysteine (L/C) confersresistance to bicalutamide (Hara, T., Miyazaki, J., Araki, H., Yamaoka,M., Kanzaki, N., Kusaka, M., and Miyamoto, M. (2003). Novel mutations ofandrogen receptor: a possible mechanism of bicalutamide withdrawalsyndrome. Cancer research 63, 149-153), while T877 mutation results inresistance to hydroxyflutamide (Tan, J., Sharief, Y., Hamil, K. G.,Gregory, C. W., Zang, D. Y., Sar, M., Gumerlock, P. H., deVere White, R.W., Pretlow, T. G., Harris, S. E., et al. (1997). Dehydroepiandrosteroneactivates mutant androgen receptors expressed in the androgen-dependenthuman prostate cancer xenograft CWR22 and LNCaP cells. Mol Endocrinol11, 450-459). 17 potently inhibited the R1881-induced wildtype ARtransactivation with much higher potency than enzalutamide (FIG. 13A).While 17 effectively antagonized both wildtype and mutant ARscomparably, (FIG. 13B). 17 inhibited glucocorticoid receptor (GR) andmineralocorticoid receptor (MR) transactivation only at ˜10 μM (FIG.13C).

Example 3 AR Degradation Activity

Compounds 17 and 14 were tested for their effect on AR proteinexpression. While 17 drastically reduced the levels of AR proteinfollowing 24 hours of treatment in LNCaP cells (serum starved andtreated with 0.1 nM R1881) as measured by Western blot (FIG. 1A),bicalutamide or enzalutamide (MDV-3100) had no effect at an equalconcentration (FIGS. 1E (VCaP) and 1F (LNCaP)). Under identicalconditions, the lowest concentration of 17 that was capable of reducingAR protein levels in LNCaP cells was 100 nM (FIG. 1B). Similar ARprotein down-regulation was observed under hormone replete conditions inLNCaP (FIG. 1C), in HeLa cells infected with an adenovirus expressinghigh levels of wt-AR (FIG. 1D; suggesting activity in CPRC where AR genehas been activated) as well as in wt-AR expressing VCaP cells 14 (FIG.1E). 14 also similarly reduced the AR levels in LNCaP cells, requiringas little as 2 hours of treatment and matching closely the time courseof 17-AAG (FIG. 1F). Neither bicalutamide nor MDV-3100 (enzalutamide)had any effect on AR protein levels even after 24 hours of treatment.Likewise, 17 demonstrated more potent and complete AR degradation inLNCaP cells than the reported SARDs ASC-J9 (not shown) and ARN-509 (FIG.2A), and AR antagonist enzalutamide (not shown) (FIG. 2A). 17 and 14treatment in LNCaP cells resulted in small reductions in AR mRNA levels,but only at 10 μM and not at 1 μM. Unlike the HSP-90 inhibitor 17-AAG,17 treatment did not affect PR (FIG. 4E), GR (not shown) and ERα (FIG.4F) protein levels (FIG. 4).

FIG. 9 depicts that 49 in the presence of R1881 degrades AR in LNCaPcells. LNCaP cells were plated in 6 well plates at 1 million cells/well.The cells were maintained in serum free conditions for 3 days. The cellswere treated as indicated in the figure, harvested, protein extracted,and Western blotted for AR. 49 and other SARDs of this inventiondemonstrated selective degradation of AR (i.e., SARD activity) in the nMrange, i.e., at concentrations comparable to their antagonist IC₅₀values. LNCaP cells are known to express the AR mutant T877A,demonstrating the ability to degrade antiandrogen resistance conferringmutant androgen receptors.

FIG. 10 depicts that 49 degrades AR in RV22-1 cells. 22RV-1 cells wereplated in 6 well plate at 1-1.5 million cells/well in growth medium(RPMI+10% FBS). Next day, medium was changed and treated with vehicle ora dose response of 49. After overnight treatment (12-16 hrs), cells werewashed in ice cold PBS and harvested by scrapping in 1 mL PBS. Cellswere pelleted, protein extracted, quantified using BCA assay, and equalquantity of protein was fractionated on a SDS-PAGE. The proteins weretransferred to nylon membrane and Western blotted with AR antibody (N20from SCBT) and actin antibody. 49 was capable of degrading full-lengthandrogen receptor (AR-FL) and truncated AR (AR-SV) in 22RV-1 cells,suggesting that SARDs will be able to overcome AR-V7 dependent prostatecancers.

LNCaP cells are known to express the AR mutant T877A, demonstrating theability of the SARDs of this invention to degrade antiandrogenresistance conferring mutant androgen receptors (i.e., advanced prostatecancers and CRPC). 14, 17 and 49 were capable of degrading full-lengthandrogen receptor (AR-FL) and truncated AR (AR-V7) in 22RV-1 cells,suggesting that SARDs will be able to overcome AR-V7 dependent prostatecancers (i.e., CRPC).

These SARD activity demonstrations suggest the compounds of thisinvention are able to degrade a variety of AR variants, and hence shouldprovide the ability to inhibit the AR-axis activity whether it isandrogen-dependent or androgen-independent. Degradation of the ARremoves the possibility of promiscuous activation of mutant ARs,activation by intracellular processes such as signal transduction andkinase activation, etc.; and suggests that the SARDs should also degradethe polyQ polymorphism in hyperandrogenic dermatologic disorders(shortened polyQ) or Kennedy's disease (extended polyQ), providing arationale for treating either type of diseases by destroying the AR inthe affected tissues (skin and neuromuscular system, respectively).

Example 4 Effect on PCa Gene Expression and Cell Growth

The ability of these novel antagonists to inhibit AR-regulated geneexpression was measured in LNCaP, a PCa cell line known to harbor aT877A mutation (Table 5).

TABLE 5 Effect of antagonists on AR-target gene expression and growth inLNCaP cells. Gene Expression + 0.1 nM R1881 (IC₅₀ nM) Gene BicalutamideMDV-3100 Cmpd 17 PSA 783.7 1,019.3 198.5 NKx3.1 755.8 1,142.8 176.0FKBP51 270.9 76.8 51.8 TMPRSS2 831.4 823.7 128.1 Growth 872 469

Consistent with binding and transcriptional activation assays, 17significantly inhibited agonist-stimulated expression of PSA, NKx3.1,FKBP51, and TMPRSS2 genes (IC₅₀ values of 198.5, 176.0, 51.8, and 128.1nM, respectively).

TABLE 6 Cmpd 17 Day Growth 17-AAG 7 Day Growth Enzalutamide 7 Day GrowthCell Line/ (IC₅₀, μM) (IC₅₀, μM) (IC₅₀, μM) R1881 Veh 0.01 0.1 10 Veh0.01 0.1 10 Veh 0.01 0.1 10 VCaP 2.99 2.92 2.48 3.82 0.657 0.414 0.7781.06 0.742 1.53 >3 >10 LNCaP 0.78 0.49 0.47 — 0.260 0.292 0.157 — 0.2810.656 3.02 — PC-3 >10 >10 >10 >10 0.307 0.221 0.257 0.542 >10 >10 >10>10

Similar activity was demonstrated in LNCaP cells with 14 (not shown).Consistent with inhibition of gene expression, 17 inhibited growth ofAR-positive, androgen-dependent PCa cells (LNCaP and VCaP) in both thehormone-deplete and hormone-replete states (Table 6). Unlike the HSP-90inhibitor 17-AAG, 17 had no effects in the AR negative PC cell line,PC-3 (Table 6). See also FIG. 2B for a bar graph that depicts that 17inhibited growth of LNCaP cells with comparable efficacy and potency asenzalutamide and ARN-509.

Example 5 SARDs Degrade AR-SV in 22RV-1 Cells

The effect of SARD treatment on the AR levels was also measured inandrogen-refractory 22RV-1 PCa cells. These cells express both AR-FL andthe low molecular weight splice variant species of the AR (AR-SV) anddepend on the AR-SV for growth. 17 (FIGS. 3A and 3B) and 14 (FIG. 3C)completely down regulated both AR-FL and AR-SV species (FIG. 3) incontrast to the limited effects of 17-AAG only on AR-FL (not shown).MDV-3100 treatment did not affect levels of either AR species (FIG. 3C),and ASC-J9 and ARN-509 did not reduce AR-V7 levels. Growth assayperformed in 22RV-1 cells treated with SARDs in the presence or absenceof 0.1 nM R1881 demonstrated that SARDs, but not MDV-3100, bicalutamide,enzalutamide, or ARN-509, markedly suppressed the growth of 22RV-1 cells(Table 7). The AR-SV variant (e.g., AR-V7; Cancer Res. 2013 Jan. 15;73(2): 483-489) lacks the LBD and so SARD activity against AR-SV mustoperate through an alternative binding and degradation domain (BDD).

TABLE 7 Effect of SARDs on AR transactivation and growth in 22RV-1cells. Transactivation Growth Compound IC₅₀ (nM) IC₅₀ (nM) Bicalutamide3133.52 >10,000 Enzalutamide 101.87 >10,000 Cmpd 17 56.36 2642 ARN-50964.54 >10,000 ASC-J9 1026.91 >10,000

FIG. 4 depicts degradation of AR by SARDs under varying conditions(A-D), without degradation of other receptors (E-F). (A.) and (B.) LNCaPcells were serum starved and treated with compound 17 (10 uM in panel Aand a dose response in panel B) in the presence or absence of R1881.Bicalutamide was used as a negative control. Cells were harvested,protein extracted, and Western blotted for AR and actin. (C.) LNCaPcells were plated in full serum and treated with compound 17 (doseresponse). Cells were harvested, protein extracted, and Western blottedfor AR and actin. (D.) HeLa cells were infected with adenoviruscontaining AR and were treated with compound 17 in the presence orabsence of R1881. Cells were harvested, protein extracted, and Westernblotted for AR and actin. (E.) and (F.) SARDs do not degrade othernuclear receptors. T47D (left panel) and MCF-7 (right panel) cells wereplated in full serum and treated with compound 17 (dose response). Cellswere harvested, protein extracted, and Western blotted for PR(progesterone receptor) or ER-α (estrogen receptor-alpha) and actin.

The reproducibility of the effect of the SARD compounds of thisinvention on the AR expression was evaluated under various experimentalconditions (LNCaP cells in full serum, wildtype AR in HeLa cells, andothers). 17 degradation effect was captured when the Western blot wasperformed for the AR with N20 antibody and actin (FIG. 14A). Westernblot was performed with a different antibody targeting the C-terminus(AR C₁₉; FIG. 14B), indicating that the degradation is not due to themasking of the antibody binding site by the SARDs.

To exclude that the degradation effects are not due to transcriptionalinhibition, LNCaP cells were treated with 17 in the presence of R1881under conditions similar to that used for Western blot. 17 failed toalter the AR mRNA expression, while it robustly inhibited the expressionof the AR-target gene, FKBP5 (FIG. 15).

Example 6 Liver Metabolism and Pharmacokinetic (PK) Properties of SARDs

To evaluate the metabolic stability parameters such as half-life andclearance, human, rat, and dog liver microsomes were incubated with 17and 14 for 60 min. Both molecules had very short half-lives between 5and 10 min and high clearance (Table 8).

TABLE 8 DMPK studies with SARDs of the invention. Rat PK CL_obs IV AUCall Rat LM - P1 Rat LM - P1 Rat LM - P1 Rat LM - P1 SARD (mL/min/kg)(min* μg/mL) PO_F % Half Life (min) CL (μL/min/mg) Half Life (min) CL(μL/min/mg) 17 30.4 323.4 0.7 4.6 150.9 2.5 281.4 14 9.4 1067.9 0.4 7.099.5 2.6 266.0

PK studies in rats to follow up the metabolism data also demonstratedthat the SARDs have very low bioavailability and area under the curve(AUC) (Table 8), indicating that their PK properties need to be improvedby structural modifications and optimal formulation in order to obtainsystemic exposures necessary for oral administration and efficacy for,e.g., prostate cancer. However, the high potency and efficacy of theselective androgen receptor degradation coupled with the low half-livesand high metabolic clearances suggest that topical administration of thecompounds of this invention could exert strong (high potency and highefficacy) antiandrogenic effects when applied topically directly toaffected areas. E.g., topical administration to localized skin lesionssuch as in acne, seborrheic dermatitis, hirsutism, etc. could degradethe AR in these tissues, thereby countering the hyperandrogenism,without risk of significant systemic exposures that could result inuntoward anti-anabolic or sexual side effects.

Example 7 Effects on Androgen-Dependent Tissues in Intact Male Rats

To measure in vivo antagonist activity, 17 and 14 were administered tointact male rats via intravenous (i.v.) bolus injection (FIG. 5). Due tohigh clearance, studies with oral administration of these moleculesfailed to significantly affect any androgen-dependent tissues such asprostate, seminal vesicles, or levator ani. Hence, the study wasconducted with i.v. administration to derive evidence of in vivoactivity. Following 3 days of therapy, reductions in prostate weightnormalized to body weight were observed in 1 of 2 17-treated animals,and 3 of 4 14-treated animals as compared to vehicle-treated controls.Reductions of greater magnitude in seminal vesicle weight were observedin 4 of 4 animals treated with 14 with no changes in 17 animals. Bothcompounds tested varied greatly in the exposures following 23 mpk 14 and23 mpk 17 doses resulting in 32 and 13 μM*hr exposures, respectively.These studies indicate the requirement for molecules with betterbioavailability or formulation that will enhance the oralbioavailability and efficacy in achieving systemic antiandrogeniceffects.

Example 8 SARDs do not Inhibit Transactivation of Other Receptors

HEK-293 cells were transfected with the indicated receptors and GRE-LUCand CMV-renilla luc. Cells were treated 24 hrs after transfection andluciferase assay performed 48 hrs after transfection. SARDs did notinhibit transactivation of other receptors until 10 uM (FIG. 6).

Example 9 SARDs Inhibit Recruitment of AR to the Promoter and EnhancerElements of Androgen Responsive Genes

LNCaP cells were serum starved for 3 days and treated as indicated abovewith SARD (compound 17) or bicalutamide at 10 uM in the presence orabsence of 0.1 nM R1881. Proteins were cross-linked to DNA and chromatinimmunoprecipitation studies were conducted with AR and RNA-Pol IIantibodies. 17 inhibited recruitment to the promoter or enhancerelements of androgen responsive genes such as PSA, FKBP, and TMPRSS2(FIG. 7A). SARDs degrade AR. LNCaP cells were serum starved for 3 daysand treated as indicated above with SARD (17) at 10 uM in the presenceor absence of 0.1 nM R1881. Cells were fixed and immunofluorescence forAR performed. Nucleus was stained with DAPI. SARDs did not abrogate ARtranslocation to the nucleus but did decrease levels of AR in thenucleus upon treatment with an agonist R1881 (FIG. 7B).

Inhibition of AR recruitment to PSA enhancer and RNA Pol II recruitmentto PSA promoter was also observed with 17 (FIGS. 16A, 16B).

Example 10 SARDs Inhibited LNCaP Cell Growth by Non-Competitive Bindingto AR

LNCaP cells were plated in serum free medium and were treated withincreasing concentrations of enzalutamide or 17 in the presence of adose range of R1881. Seven days after treatment, cells were fixed andgrowth measured by WST-1 assay. SARDs inhibited LNCaP cell growth by anapparent non-competitive binding to AR (FIG. 8). As expected,enzalutamide IC₅₀ values for cell growth inhibition increased withincreased amounts of R1881. However, the IC₅₀ values for cell growthinhibition for 17 did not increase with amounts of R1881, possiblyindicating that R1881 and 17 were not competing for the same bindingsite on AR.

Example 11 SARDs Bind to the AR-AF1

There are two tryptophan residues and up to 12 tyrosine residues in theAF1 of the AR. This has allowed the study of the folding properties ofthis domain using intrinsic steady state fluorescence emission spectra.Excitation at 287 nm excites both tyrosine and tryptophan residues. Theemission maximum (λmax) for the tryptophan is sensitive to the exposureto solvent. In the presence of the natural osmolyte TMAO there is acharacteristic ‘blue shift’ consistent with the tryptophan residuesbeing less solvent exposed and a loss of the shoulder (—307 nm) fortyrosine as there is increased energy transfer to tryptophan as thepolypeptide folds. To test if the compounds, enobosarm (negativecontrol), and 17 interact with AF-1 and/or alter the folding of thisdomain the steady state fluorescence was measured for each compound withAR-AF1 alone or the presence of TMAO (3 M) or urea (4 or 6 M). 1 μM ofAR-AF1 and 5 μM of the individual compounds were used, and preincubatedfor at least 30 minutes prior to measuring the emission spectra. Theemission spectra were all corrected for buffer alone or buffer withTMAO/urea/compounds as necessary.

FIG. 11 depicts that SARDs bind to the AR-AF1. FIG. 11A: The emissionspectra were all corrected for buffer alone or buffer withTMAO/urea/compounds as necessary. There was no dramatic effect ofenobosarm (left panel) on the λ_(max) for tryptophan, while 17 (rightpanel) reduces the wavelength (i.e., a ‘blue shift’), indicating that 17binds to the AF-1 and enobosarm does not bind to AF-1. FIG. 11B: LeftPanel: Dose-dependent shift in the fluorescence intensity, i.e.,fluorescent quenching, by 17 when incubated with AR AF-1. Thefluorescence shoulder observed at 307 nm, which corresponds to tyrosineresidues in the AF-1, is shifted by 17. The overall fluorescence is alsomarkedly altered by 17.

Right Panel: Data shown in the left panel was plotted as difference influorescence between control and compound 17 treated samples(fluorescence in the absence of compound—fluorescence in the presence ofcompound). A dose dependent increase was observed in the presence of 17indicating interaction between 17 and AF1.

Example 12 AF1 Binding—External Validation (VIB)

Target Molecule:

Compound 17 was delivered dissolved in DMSO at 10 μM.

Experimental Setup

Purified H6-AF1 was biotinylated with N-hydroxysuccinimide(NHS)-PEG4-biotin at an estimated protein-biotylation ratio of 1:1.Bio-layer interferometry (BLI) was used to screen for binding of smallmolecule to biotinylated protein using the Octet 96RED system(Fort{tilde over (e)}Bio®). Biotinylated H6-AF1 was immobilized on superstreptavidin (SSA) biosensors at full saturation level in order todetect signals from binding of small molecule. Biosensors loaded withAF1 were used in parallel to screen for binding of 17.

Results

Raw data measurements from binding of Compound 17 to AF1 are shown inFIG. 12. The data shows the AF1 loaded biosensors gave a stronger signalthan any of the reference sensors at 50 nM concentrations. At higherconcentration measurements were not possible because of the solubilityissue with the compound.

³²

While certain features of the invention have been illustrated anddescribed herein, many modifications, substitutions, changes, andequivalents will now occur to those of ordinary skill in the art. It is,therefore, to be understood that the appended claims are intended tocover all such modifications and changes as fall within the true spiritof the invention.

What is claimed is:
 1. A method of treating, suppressing, reducing theincidence, reducing the severity, or inhibiting the progression ofAR-expressing cancer in a subject, comprising administering to saidsubject a therapeutically effective amount of compound 17

or its optical isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, hydrate or any combination thereof.
 2. The method ofclaim 1, wherein said cancer is a cancer associated with partialandrogen insensitivity syndromes (PAIS), cancer of the fallopian tubesor peritoneum, salivary gland cancer, esophageal cancer, bladder cancer,melanoma, mantle cell lymphoma, hepatocellular carcinoma, renal cellcarcinoma, non-small cell lung cancer (NSCLC), gastric cancer, and/orcolon cancer.
 3. The method of claim 2, wherein the cancer associatedwith partial androgen insensitivity syndromes (PAIS) is gonadal tumorsand/or seminoma.
 4. A method of treating, suppressing, reducing theincidence, reducing the severity, or inhibiting the progression ofKennedy's disease in a subject, comprising administering to said subjecta therapeutically effective amount of compound 17

or its optical isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, hydrate or any combination thereof.
 5. A method oftreating, suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of amyotrophic lateral sclerosis (ALS) in asubject, comprising administering to said subject a therapeuticallyeffective amount of compound

or its optical isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, hydrate or any combination thereof.
 6. A method oftreating, suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of AR-positive cancer that is resistant totreatment with an androgen receptor antagonist and/or a lyase inhibitor,comprising administering to said subject a therapeutically effectiveamount of compound 17

or its optical isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, hydrate or any combination thereof.
 7. A method oftreating abdominal aortic aneurysm (AAA) in a subject, comprisingadministering to said subject a therapeutically effective amount ofcompound

or its optical isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, hydrate or any combination thereof.
 8. A method oftreating, suppressing, reducing the incidence, reducing the severity, orinhibiting the progression of a hyperandrogenic hormonal condition in afemale, comprising administering to said subject a therapeuticallyeffective amount of compound

or its optical isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, hydrate or any combination thereof, wherein saidhyperandrogenic hormonal condition in a female is precocious puberty,early puberty, dysmenorrhea, amenorrhea, multilocular uterus syndrome,endometriosis, hysteromyoma, abnormal uterine bleeding, early menarche,fibrocystic breast disease, fibroids of the uterus, ovarian cysts,polycystic ovary syndrome, pre-eclampsia, eclampsia of pregnancy,preterm labor, premenstrual syndrome, and/or vaginal dryness.
 9. Atopical pharmaceutical composition comprising compound 17

or its optical isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, hydrate or any combination thereof, and apharmaceutically acceptable carrier.
 10. The topical pharmaceuticalcomposition of claim 9, wherein said composition is in the form of asolution, lotion, salve, cream, ointment, liposome, spray, gel, foam,roller stick, cleansing soap or bar, emulsion, mousse, aerosol, shampoo,or any combination thereof.